Extended release biodegradable ocular implants

ABSTRACT

Biodegradable implants sized and suitable for implantation in an ocular region or site and methods for treating ocular conditions. The implants provide an extended release of an active agent at a therapeutically effective amount for a period of time between 50 days and one year, or longer.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/048,255 filed on Oct. 8, 2013, which is a continuation of U.S.application Ser. No. 10/837,355 filed on Apr. 30, 2004, issued as U.S.Pat. No. 8,685,435 on Apr. 1, 2014, the entire disclosure of each ofwhich is incorporated herein by reference.

BACKGROUND

This invention relates to implants and methods for treating an ocularcondition. In particular the present invention relates to implants andmethods for treating an ocular condition by implanting into an ocularregion or site an extended release bioerodible implant comprising anactive agent and a bioerodible polymer. The bioerodible implants of thisinvention have varying and extended release rates to provide forimproved kinetics of release of one or more active (therapeutic) agentsover time.

An ocular condition can include a disease, aliment or condition whichaffects or involves the eye or one of the parts or regions of the eye.Broadly speaking the eye includes the eyeball and the tissues and fluidswhich constitute the eyeball, the periocular muscles (such as theoblique and rectus muscles) and the portion of the optic nerve which iswithin or adjacent to the eyeball. An anterior ocular condition is adisease, ailment or condition which affects or which involves ananterior (i.e. front of the eye) ocular region or site, such as aperiocular muscle, an eye lid or an eye ball tissue or fluid which islocated anterior to the posterior wall of the lens capsule or ciliarymuscles. Thus, an anterior ocular condition primarily affects orinvolves, the conjunctiva, the cornea, the conjunctiva, the anteriorchamber, the iris, the posterior chamber (behind the retina but in frontof the posterior wall of the lens capsule), the lens or the lens capsuleand blood vessels and nerve which vascularize or innervate an anteriorocular region or site. A posterior ocular condition is a disease,ailment or condition which primarily affects or involves a posteriorocular region or site such as choroid or sclera (in a position posteriorto a plane through the posterior wall of the lens capsule), vitreous,vitreous chamber, retina, optic nerve (i.e. the optic disc), and bloodvessels and nerves which vascularize or innervate a posterior ocularregion or site.

Thus, a posterior ocular condition can include a disease, ailment orcondition, such as for example, macular degeneration (such asnon-exudative age related macular degeneration and exudative age relatedmacular degeneration); choroidal neovascularization; acute macularneuroretinopathy; macular edema (such as cystoid macular edema anddiabetic macular edema); Behcet's disease, retinal disorders, diabeticretinopathy (including proliferative diabetic retinopathy); retinalarterial occlusive disease; central retinal vein occlusion; uveiticretinal disease; retinal detachment; ocular trauma which affects aposterior ocular site or location; a posterior ocular condition causedby or influenced by an ocular laser treatment; posterior ocularconditions caused by or influenced by a photodynamic therapy;photocoagulation; radiation retinopathy; epiretinal membrane disorders;branch retinal vein occlusion; anterior ischemic optic neuropathy;non-retinopathy diabetic retinal dysfunction, retinitis pigmentosa andglaucoma. Glaucoma can be considered a posterior ocular conditionbecause the therapeutic goal is to prevent the loss of or reduce theoccurrence of loss of vision due to damage to or loss of retinal cellsor optic nerve cells (i.e. neuroprotection).

An anterior ocular condition can include a disease, ailment orcondition, such as for example, aphakia; pseudophakia; astigmatism;blepharospasm; cataract; conjunctival diseases; conjunctivitis; cornealdiseases; corneal ulcer; dry eye syndromes; eyelid diseases; lacrimalapparatus diseases; lacrimal duct obstruction; myopia; presbyopia; pupildisorders; refractive disorders and strabismus. Glaucoma can also beconsidered to be an anterior ocular condition because a clinical goal ofglaucoma treatment can be to reduce a hypertension of aqueous fluid inthe anterior chamber of the eye (i.e. reduce intraocular pressure).

The present invention is concerned with and directed to an extendedrelease implant and methods for the treatment of an ocular condition,such as an anterior ocular condition or a posterior ocular condition orto an ocular condition which can be characterized as both an anteriorocular condition and a posterior ocular condition.

Therapeutic compounds useful for the treatment of an ocular conditioncan include active agents with, for example, an anti-neoplastic,anti-angiogenesis, kinase inhibition, anticholinergic, anti-adrenergicand/or anti-inflammatory activity.

Macular degeneration, such as age related macular degeneration (“AMD”)is the leading cause of blindness in the world. It is estimated thatthirteen million Americans have evidence of macular degeneration.Macular degeneration results in a break down the macula, thelight-sensitive part of the retina responsible for the sharp, directvision needed to read or drive. Central vision is especially affected.Macular degeneration is diagnosed as either dry (atrophic) or wet(exudative). The dry form of macular degeneration is more common thanthe wet form of macular degeneration, with about 90% of AMD patientsbeing diagnosed with dry AMD. The wet form of the disease usually leadsto more serious vision loss. Macular degeneration can produce a slow orsudden painless loss of vision. The cause of macular degeneration is notclear. The dry form of AMD may result from the aging and thinning ofmacular tissues, depositing of pigment in the macula, or a combinationof the two processes. With wet AMD, new blood vessels grow beneath theretina and leak blood and fluid. This leakage causes retinal cells todie and creates blind spots in central vision.

Macular edema (“ME”) can result in a swelling of the macula. The edemais caused by fluid leaking from retinal blood vessels. Blood leaks outof the weak vessel walls into a very small area of the macula which isrich in cones, the nerve endings that detect color and from whichdaytime vision depends. Blurring then occurs in the middle or just tothe side of the central visual field. Visual loss can progress over aperiod of months. Retinal blood vessel obstruction, eye inflammation,and age-related macular degeneration have all been associated withmacular edema. The macula may also be affected by swelling followingcataract extraction. Symptoms of ME include blurred central vision,distorted vision, vision tinted pink and light sensitivity. Causes of MEcan include retinal vein occlusion, macular degeneration, diabeticmacular leakage, eye inflammation, idiopathic central serouschorioretinopathy, anterior or posterior uveitis, pars planitis,retinitis pigmentosa, radiation retinopathy, posterior vitreousdetachment, epiretinal membrane formation, idiopathic juxtafovealretinal telangiectasia, Nd:YAG capsulotomy or iridotomy. Some patientswith ME may have a history of use of topical epinephrine orprostaglandin analogs for glaucoma. The first line of treatment for MEis typically anti-inflammatory drops topically applied.

An anti-inflammatory (i.e. immunosuppressive) agent can be used for thetreatment of an ocular condition, such as a posterior ocular condition,which involves inflammation, such as an uveitis or macula edema. Thus,topical or oral glucocorticoids have been used to treat uveitis. A majorproblem with topical and oral drug administration is the inability ofthe drug to achieve an adequate (i.e. therapeutic) intraocularconcentration. See e.g. Bloch-Michel E. (1992). Opening address:intermediate uveitis, In Intermediate Uveitis, Dev. Ophthalmol, W. R. F.Böke et al. editors., Basel: Karger, 23:1-2; Pinar, V., et al. (1997).Intraocular inflammation and uveiti” In Basic and Clinical ScienceCourse. Section 9 (1997-1998) San Francisco: American Academy ofOphthalmology, pp. 57-80, 102-103, 152-156; Böke, W. (1992). Clinicalpicture of intermediate uveitis, In Intermediate Uveitis, Dev.Ophthalmol. W. R. F. Böke et al. editors., Basel: Karger, 23:20-7; andCheng C-K et al. (1995). Intravitreal sustained-release dexamethasonedevice in the treatment of experimental uveitis, Invest. Ophthalmol.Vis. Sci. 36:442-53.

Systemic glucocorticoid administration can be used alone or in additionto topical glucocorticoids for the treatment of uveitis. However,prolonged exposure to high plasma concentrations (administration of 1mg/kg/day for 2-3 weeks) of steroid is often necessary so thattherapeutic levels can be achieved in the eye.

Unfortunately, these high drug plasma levels commonly lead to systemicside effects such as hypertension, hyperglycemia, increasedsusceptibility to infection, peptic ulcers, psychosis, and othercomplications. Cheng C-K et al. (1995). Intravitreal sustained-releasedexamethasone device in the treatment of experimental uveitis, Invest.Ophthalmol. Vis. Sci. 36:442-53; Schwartz, B. (1966). The response ofocular pressure to corticosteroids, Ophthalmol. Clin. North Am.6:929-89; Skalka, H. W. et al. (1980). Effect of corticosteroids oncataract formation, Arch Ophthalmol 98:1773-7; and Renfro, L. et al.(1992). Ocular effects of topical and systemic steroids, DermatologicClinics 10:505-12.

Additionally, delivery to the eye of a therapeutic amount of an activeagent can be difficult, if not impossible, for drugs with short plasmahalf-lives since the exposure of the drug to intraocular tissues islimited. Therefore, a more efficient way of delivering a drug to treat aposterior ocular condition is to place the drug directly in the eye,such as directly into the vitreous. Maurice, D. M. (1983).Micropharmaceutics of the eye, Ocular Inflammation Ther. 1:97-102; Lee,V. H. L. et al. (1989). Drug delivery to the posterior segment” Chapter25 In Retina. T. E. Ogden and A. P. Schachat eds., St. Louis: CV Mosby,Vol. 1, pp. 483-98; and Olsen, T. W. et al. (1995). Human scleralpermeability: effects of age, cryotherapy, transscleral diode laser, andsurgical thinning, Invest. Ophthalmol. Vis. Sci. 36:1893-1903.

Techniques such as intravitreal injection of a drug have shown promisingresults, but due to the short intraocular half-life of active agent,such as glucocorticoids (approximately 3 hours), intravitreal injectionsmust be frequently repeated to maintain a therapeutic drug level. Inturn, this repetitive process increases the potential for side effectssuch as retinal detachment, endophthalmitis, and cataracts. Maurice, D.M. (1983). Micropharmaceutics of the eye, Ocular Inflammation Ther.1:97-102; Olsen, T. W. et al. (1995). Human scleral permeability:effects of age, cryotherapy, transscleral diode laser, and surgicalthinning, Invest. Ophthalmol. Vis. Sci. 36:1893-1903; and Kwak, H. W.and D'Amico, D. J. (1992). Evaluation of the retinal toxicity andpharmacokinetics of dexamethasone after intravitreal injection, Arch.Ophthalmol. 110:259-66.

Additionally, topical, systemic, and periocular glucocorticoid treatmentmust be monitored closely due to toxicity and the long-term side effectsassociated with chronic systemic drug exposure sequelae. Rao, N. A. etal. (1997). Intraocular inflammation and uveitis, In Basic and ClinicalScience Course. Section 9 (1997-1998) San Francisco: American Academy ofOphthalmology, pp. 57-80, 102-103, 152-156; Schwartz, B. (1966). Theresponse of ocular pressure to corticosteroids, Ophthalmol Clin North Am6:929-89; Skalka, H. W. and Pichal, J. T. (1980). Effect ofcorticosteroids on cataract formation, Arch Ophthalmol 98:1773-7;Renfro, L and Snow, J. S. (1992). Ocular effects of topical and systemicsteroids, Dermatologic Clinics 10:505-12; Bodor, N. et al. (1992). Acomparison of intraocular pressure elevating activity of loteprednoletabonate and dexamethasone in rabbits, Current Eye Research 11:525-30.

U.S. Pat. No. 6,217,895 discusses a method of administering acorticosteroid to the posterior segment of the eye, but does notdisclose a bioerodible implant.

U.S. Pat. No. 5,501,856 discloses controlled release pharmaceuticalpreparations for intraocular implants to be applied to the interior ofthe eye after a surgical operation for disorders in retina/vitreous bodyor for glaucoma.

U.S. Pat. No. 5,869,079 discloses combinations of hydrophilic andhydrophobic entities in a biodegradable sustained release implant, anddescribes a polylactic acid polyglycolic acid (PLGA) copolymer implantcomprising dexamethasone. As shown by in vitro testing of the drugrelease kinetics, the 100-120 μg 50/50 PLGA/dexamethasone implantdisclosed did not show appreciable drug release until the beginning ofthe fourth week, unless a release enhancer, such as HPMC was added tothe formulation.

U.S. Pat. No. 5,824,072 discloses implants for introduction into asuprachoroidal space or an avascular region of the eye, and describes amethylcellulose (i.e. non-biodegradable) implant comprisingdexamethasone. WO 9513765 discloses implants comprising active agentsfor introduction into a suprachoroidal or an avascular region of an eyefor therapeutic purposes.

U.S. Pat. Nos. 4,997,652 and 5,164,188 disclose biodegradable ocularimplants comprising microencapsulated drugs, and describes implantingmicrocapsules comprising hydrocortisone succinate into the posteriorsegment of the eye.

U.S. Pat. No. 5,164,188 discloses encapsulated agents for introductioninto the suprachoroid of the eye, and describes placing microcapsulesand plaques comprising hydrocortisone into the pars plana. U.S. Pat.Nos. 5,443,505 and 5,766,242 discloses implants comprising active agentsfor introduction into a suprachoroidal space or an avascular region ofthe eye, and describes placing microcapsules and plaques comprisinghydrocortisone into the pars plana.

Zhou et al. disclose a multiple-drug implant comprising 5-fluorouridine,triamcinolone, and human recombinant tissue plasminogen activator forintraocular management of proliferative vitreoretinopathy (PVR). Zhou,T, et al. (1998). Development of a multiple-drug delivery implant forintraocular management of proliferative vitreoretinopathy, Journal ofControlled Release 55: 281-295.

U.S. Pat. No. 6,046,187 discusses methods and compositions formodulating local anesthetic by administering one or moreglucocorticosteroid agents before, simultaneously with or after theadministration of a local anesthetic at a site in a patient.

U.S. Pat. No. 3,986,510 discusses ocular inserts having one or moreinner reservoirs of a drug formulation confined within a bioerodibledrug release rate controlling material of a shape adapted for insertionand retention in the “sac of the eye,” which is indicated as beingbounded by the surfaces of the bulbar conjunctiva of the sclera of theeyeball and the palpebral conjunctiva of the eyelid, or for placementover the corneal section of the eye.

U.S. Pat. No. 6,369,116 discusses an implant with a release modifierinserted in a scleral flap.

EP 0 654256 discusses use of a scleral plug after surgery on a vitreousbody, for plugging an incision.

U.S. Pat. No. 4,863,457 discusses the use of a bioerodible implant toprevent failure of glaucoma filtration surgery by positioning theimplant either in the subconjunctival region between the conjunctivalmembrane overlying it and the sclera beneath it or within the scleraitself within a partial thickness sclera flap.

EP 488 401 discusses intraocular implants, made of certain polylacticacids, to be applied to the interior of the eye after a surgicaloperation for disorders of the retina/vitreous body or for glaucoma.

EP 430539 discusses use of a bioerodible implant which is inserted inthe suprachoroid.

Significantly, it is known that PLGA co-polymer formulations of abioerodible polymer comprising an active agent typically release theactive agent with a characteristic sigmoidal release profile (as viewedas time vs percent of total active agent released), that is after arelatively long initial lag period (the first release phase) when littleif any active agent is released, there is a high positive slope periodwhen most of the active agent is released (the second release phase)followed by another near horizontal (third) release phase, when the drugrelease reaches a plateau.

Thus, there is a need for a therapeutically effective extended releaseimplant for the treatment of an ocular condition, such as posteriorocular condition. In particular, there is a need for effective deliveryover an extended duration, for example, time periods extending up to 60days, 90 days, 120 days, 6 months, 8 months, 12 months or more,preferably with maintenance of a therapeutic drug level at a desiredposterior ocular region or site. Such extended delivery of an activeagent can be advantageous to prevent recurrence of the inflammatory orother posterior ocular condition treated. It can also minimize thenumber of surgical interventions required by the patient over time totreat the condition, as compared to the use of implants having shorterrelease profiles.

SUMMARY

The present invention meets these and other needs and provides forbioerodible implants and implant systems that can continually, orsubstantially continually, release active agent, such as the steroidalanti-inflammatory agent dexamethasone, at levels corresponding to atleast about 5 ng/ml (and up to about 100 ng/ml) of dexamethasone ordexamethasone equivalent in the vitreous humor for a period of betweenabout 30 days to about 360 days or more to treat an ocular condition,such as a retinal disease. In certain variations, consistent releaselevels of at least 10 to 50 ng/ml of dexamethasone or dexamethasoneequivalent are achieved. In other variations, a continuous orsubstantially active agent release level can be achieved in vivo (i.e.in the vitreous) for at least about 90 days or more, 120 days or more, 6months or more, 8 months or more, and 12 months or more.

Definitions

The following terms as used herein have the following meanings:

“About” means approximately or nearly and in the context of a numericalvalue or range set forth herein means ±10% of the numerical value orrange recited or claimed.

“Active agent” and “drug” are used interchangeably and refer to anysubstance used to treat an ocular condition.

“Bioerodible polymer” means a polymer which degrades in vivo, andwherein erosion of the polymer over time is required to achieve theactive agent release kinetics according to the present invention. Thus,hydrogels such as methylcellulose which act to release drug throughpolymer swelling are specifically excluded from the term “bioerodible(or biodegradable) polymer”. The words “bioerodible” and “biodegradable”are synonymous and are used interchangeably herein.

“Concentration equivalent to dexamethasone”, or “dexamethasoneequivalent” means a concentration of an active agent, such as asteroidal anti-inflammatory agent, necessary to have approximately thesame efficacy in vivo as a particular dose of dexamethasone. Forexample, hydrocortisone is approximately twenty five fold less potentthan dexamethasone, and thus a 25 mg dose of hydrocortisone would beequivalent to a 1 mg dose of dexamethasone. One of ordinary skill in theart would be able to determine the concentration equivalent todexamethasone for a particular steroidal anti-inflammatory agent fromone of several standard tests known in the art. Relative potencies ofselected corticosteroids may be found, for example, in Gilman, A. G., etal., eds. (1990). Goodman and Gilman's: The Pharmacological Basis ofTherapeutics. 8th Edition, Pergamon Press: New York, p. 1447.

“Cumulative release profile” means to the cumulative total percent of anactive agent released from an implant into an ocular region or site invivo over time or into a specific release medium in vitro over time.

“Extended” as in “extended period” or “extended release” means for aperiod of time greater than thirty days, preferably for at least 50 days(i.e. for a period of time from 50 days to 365 days), and mostpreferably for at least 60 days. An extended release can persist for ayear or more.

“Glaucoma” means primary, secondary and/or congenital glaucoma. Primaryglaucoma can include open angle and closed angle glaucoma. Secondaryglaucoma can occur as a complication of a variety of other conditions,such as injury, inflammation, vascular disease and diabetes.

“Inflammation-mediated” in relation to an ocular condition means anycondition of the eye which can benefit from treatment with ananti-inflammatory agent, and is meant to include, but is not limited to,uveitis, macular edema, acute macular degeneration, retinal detachment,ocular tumors, fungal or viral infections, multifocal choroiditis,diabetic uveitis, proliferative vitreoretinopathy (PVR), sympatheticophthalmia, Vogt Koyanagi-Harada (VKH) syndrome, histoplasmosis, anduveal diffusion.

“Injury” or “damage” are interchangeable and refer to the cellular andmorphological manifestations and symptoms resulting from aninflammatory-mediated condition, such as, for example, inflammation.

“Measured under infinite sink conditions in vitro,” means assays tomeasure drug release in vitro, wherein the experiment is designed suchthat the drug concentration in the receptor medium never exceeds 5% ofsaturation. Examples of suitable assays may be found, for example, inUSP 23; NF 18 (1995) pp. 1790-1798.

“Ocular condition” means a disease, aliment or condition which affectsor involves the eye or one or the parts or regions of the eye, such as aretinal disease. The eye includes the eyeball and the tissues and fluidswhich constitute the eyeball, the periocular muscles (such as theoblique and rectus muscles) and the portion of the optic nerve which iswithin or adjacent to the eyeball.

“Plurality” means two or more.

“Posterior ocular condition” means a disease, ailment or condition whichaffects or involves a posterior ocular region or site such as choroid orsclera (in a position posterior to a plane through the posterior wall ofthe lens capsule), vitreous, vitreous chamber, retina, optic nerve (i.e.the optic disc), and blood vessels and nerve which vascularize orinnervate a posterior ocular region or site.

“Steroidal anti-inflammatory agent” and “glucocorticoid” are usedinterchangeably herein, and are meant to include steroidal agents,compounds or drugs which reduce inflammation when administered at atherapeutically effective level.

“Substantially” in relation to the release profile or the releasecharacteristic of an active agent from a bioerodible implant as in thephrase “substantially continuous rate” of the active agent release ratefrom the implant means, that the rate of release (i.e. amount of activeagent released/unit of time) does not vary by more than 100%, andpreferably does not vary by more than 50%, over the period of timeselected (i.e. a number of days). “Substantially” in relation to theblending, mixing or dispersing of an active agent in a polymer, as inthe phrase “substantially homogenously dispersed” means that there areno or essentially no particles (i.e. aggregations) of active agent insuch a homogenous dispersal.

“Suitable for insertion (or implantation) in (or into) an ocular regionor site” with regard to an implant, means an implant which has a size(dimensions) such that it can be inserted or implanted without causingexcessive tissue damage and without unduly physically interfering withthe existing vision of the patient into which the implant is implantedor inserted.

“Therapeutic levels” or “therapeutic amount” means an amount or aconcentration of an active agent that has been locally delivered to anocular region that is appropriate to safely treat an ocular condition soas to reduce or prevent a symptom of an ocular condition.

In one variation, the present invention provides for a drug deliverysystem for treating conditions of the eye that includes a plurality ofbioerodible implants, each bioerodible implant having a unique drugrelease profile. When co-administered together, one embodiment of thisimplant system can provide an extended continuous release of drug atlevels corresponding to at least about 10 ng/ml vitreous ofdexamethasone or dexamethasone equivalent for a period of at least about120 days. In certain variations, this implant system can include threeimplants, each of which is formed from a separate poly(lactide) (i.e.PLA) polymer or poly(lactide-co-glycolide) (i.e. PLGA) copolymer.

In other variations, bioerodible implants according to the presentinvention are prepared using two or more different bioerodible polymerseach having different release characteristics. In one variation, a firstquantity of the drug or active agent is blended with a first polymer andthe resultant material is extruded and then broken into particles whichare then blended with an additional quantity of the drug or active agentand the same or a second polymer to form the final bioerodible implant,either by extrusion, injection molding or direct compression. Theresultant implant has a release profile different than that of animplant created by initially blending the polymers together and providesfor continual or substantially continual release of active agent atlevels corresponding to at least about 10 ng/ml of dexamethasone ordexamethasone equivalent for at least about 60 days.

In yet further variations, active agent can be separately blended withfirst and second bioerodible polymers to form first and seconddrug-polymer mixtures that can be co-extruded to produce implants havingfirst and second regions with differing release characteristics. Theresultant implant has a release profile different than that of animplant created by initially blending the two polymers together andprovides for continual release of drug at levels corresponding to atleast about 10 ng/ml of dexamethasone or dexamethasone equivalent for atleast about 60 days.

Our invention encompasses a drug delivery system for treating an ocularcondition, the drug delivery system can comprise: (a) at least onebioerodible implant suitable for insertion into an ocular region orsite, the bioerodible implant comprising; (i) an active agent, and; (ii)a bioerodible polymer, wherein the bioerodible implant can release atherapeutic level of the active agent into the ocular region or site fora period time between about 30 days and about 1 year. Preferably, thebioerodible implant can release the therapeutic level of the activeagent into the ocular region or site at a substantially continuous ratein vivo. More preferably, the bioerodible implant can release atherapeutic level of the active agent into the ocular region or site ata substantially continuous rate upon implantation in the vitreous for aperiod time between about 50 days and about 1 year. The active agent canbe an anti-inflammatory agent. The bioerodible polymer can be a PLGAco-polymer.

The bioerodible implant can have a weight between about 1 μg and about100 mg and no dimension less than about 0.1 mm and no dimension greaterthan about 20 mm.

A drug delivery system of claim within the scope of our invention cancomprise a plurality of bioerodible implants. The active agent can besubstantially homogenously dispersed within the bioerodible polymer orthe active agent can be associated with the bioerodible polymer in theform of particles of active agent and bioerodible polymer.

In a preferred embodiment the drug delivery system can comprise: (a) aportion of the active agent substantially homogenously dispersed withina portion of the bioerodible polymer, and; (b) a portion of the same orof a different active agent associated with a portion of same or of adifferent bioerodible polymer in the form of particles of active agentand the bioerodible polymer.

In a further embodiment the drug delivery system can comprise: (a) abioerodible implant suitable for insertion into an ocular region orsite, the bioerodible implant comprising; (i) an active agent, and; (ii)a bioerodible polymer, wherein the bioerodible implant can release atherapeutic level of the active agent upon insertion into a posteriorocular region or site for a period time of at least about 40 days.

Additionally, the drug delivery system can comprise: (a) a plurality ofbioerodible implants implantable in a posterior ocular region or site,each implant comprising; (i) an active agent, and; (ii) a bioerodiblepolymer, wherein the plurality of bioerodible implants can substantiallycontinuously release in vivo a therapeutic level of the active agent fora period time between about 5 days and about 1 year. This drug deliverysystem can comprise: (a) a first implant with a first releasecharacteristic, and; (b) a second implant with a second releasecharacteristic, wherein the first and second release characteristicsdiffer. The release profile of the drug delivery system can correspondto the sum of the first and second release profiles. Notably, this drugdelivery system can comprise: (a) a first implant with a first releasecharacteristic, (b) a second implant with a second releasecharacteristic, and; (c) a third implant with a third releasecharacteristic. And the release profile of the drug delivery system cancorrespond to the sum of the first, second and third release profiles.The drug delivery system can comprise at least two different implantswhich have different bioerodible polymers. Thus, the drug deliver systemcan comprise first, second and third bioerodible implants, wherein thefirst implant comprises a first polymer with a first average molecularweight; the second implant comprises a second polymer with a secondaverage molecular weight, and the third implant comprises a thirdpolymer with a third average molecular weight.

A particular embodiment of our invention can be a drug delivery systemfor treating a ocular condition comprising; (a) a plurality ofbioerodible implants implantable in a posterior ocular region, eachimplant comprising (i) an anti-inflammatory drug, and; (ii) abioerodible polymer, wherein the plurality of bioerodible implants cansubstantially continuously release the anti-inflammatory drug at a levelof at least about a 10 ng/ml dexamethasone equivalent for a period ofbetween 5 days and 1 year.

A preferred method for making an extended release bioerodible implantfor treating an ocular condition can be by: (a) blending and extrudingan active agent and a first bioerodible polymer to form a first solidmaterial; (b) breaking the first solid material into particles; (c)blending and extruding (or direct compressing) the particles with theactive agent with a second bioerodible polymer, to thereby form abioerodible implant, wherein the bioerodible implant can release atherapeutic level of the active agent at a substantially continuous ratefor a period time between about 50 days and about 1 year.

In another embodiment a bioerodible implant for treating a ocularcondition, the bioerodible implant can be made by: (a) blending(followed by extruding, injection molding or the like) a steroidalanti-inflammatory drug and a first bioerodible polymer to form a firstsolid material; (b) breaking the solid material into particles; (c)blending (followed by extruding, injection molding or the like) theparticles with the steroidal anti-inflammatory drug and a secondbioerodible polymer to form a bioerodible implant, wherein thebioerodible implant can release a therapeutic level of the active agentat a substantially continuous rate for a period time between about 50days and about 1 year. Such a bioerodible implant can substantiallycontinuously release the steroidal anti-inflammatory drug at adexamethasone equivalent level corresponding to at least 10 ng/ml for aperiod of at between 50 days and one year. For example, the bioerodibleimplant can continuously releases the steroidal anti-inflammatory drugat a dexamethasone equivalent corresponding to at least 50 ng/ml for aperiod of at least about 50 days.

A bioerodible implant for treating a ocular condition can also be madeas (a) a dispersion comprising an active agent dispersed with a firstbioerodible polymer, (b) a particle comprising the active agent and asecond bioerodible polymer, wherein the particle has an active agentrelease characteristic which differs from the active agent releasecharacteristic of the dispersion. Such an implant can substantiallycontinuously release the active agent at a level corresponding to atleast 10 ng/ml of dexamethasone or dexamethasone equivalent for a periodof at least about 50 days. Thus, such a bioerodible implant cansubstantially continuously release the active agent at a levelcorresponding to at least 50 ng/ml of dexamethasone or dexamethasoneequivalent for a period of at least about 50 days.

A preferred embodiment of our invention is a bioerodible implant fortreating an inflammation-mediated condition of the eye, the implantbeing made by: (a) blending a first active agent and a first bioerodiblepolymer to thereby form a first active agent polymer mixture or matrix;(b) blending a second active agent and a second bioerodible polymer tothereby form a second active agent polymer mixture or matrix; (c)co-extruding the first and second active agent polymer matrixes tothereby form a bioerodible implant containing first and second regions,the first region containing the first active agent polymer matrix, andthe second region containing the second active agent polymer matrix,wherein first and second regions have different active agent releasecharacteristics. The first active agent and the second active agent canbe the same active agent or the first active agent and the second activeagent can be different active agents. As well, the first polymer and thesecond polymer can be the same polymer or the first polymer and thesecond polymer can be different polymers. The implant can substantiallycontinuously releases active agent at levels corresponding to at least10 ng/ml of dexamethasone or dexamethasone equivalent for a period of atleast about 50 days. Thus, the implant can substantially continuouslyreleases active agent at levels corresponding to at least 50 ng/ml ofdexamethasone or dexamethasone equivalent for a period of at least about50 days.

A bioerodible implant for treating a posterior ocular condition can bemade by: (a) blending a first active agent and a first bioerodiblepolymer to thereby form a first active agent polymer mixture; (b)co-extruding the first active agent polymer mixture with a secondpolymer to thereby form a bioerodible implant containing first andsecond regions, the first region containing the first active agentpolymer mixture, and the second region containing the second polymermixture.

A bioerodible implant for treating a posterior ocular condition cancomprising: (a) a first region containing a first mixture of an activeagent and a first bioerodible polymer, and; (b) a second regioncontaining a second mixture of the active agent and a second bioerodiblepolymer, wherein the first and second regions have different activeagent release characteristics. This implant can substantiallycontinuously releases active agent at levels corresponding to at least10 ng/ml of dexamethasone or dexamethasone equivalent for a period of atleast about 50 days. Alternately, this implant of can substantiallycontinuously releases active agent at levels corresponding to at least50 ng/ml of dexamethasone or dexamethasone equivalent for a period of atleast about 50 days.

A method for treating an ocular condition according to our invention cancomprise implanting into an ocular region or site a drug delivery systemset forth herein.

DRAWINGS

FIG. 1 is a graph which shows in vitro cumulative release ofdexamethasone (as a percent of the total amount of dexamethasone loadedinto the implants) as a function of time, for the three implant system(total of 1500 μg of dexamethasone) of Examples 1 and 2.

FIG. 1B is a graph which shows the same in vitro cumulative release ofdexamethasone shown by FIG. 1, and shows as well the in vitro cumulativerelease of dexamethasone from each of the three separate (control)polymers.

FIG. 2 is a graph which shows in a comparative fashion in vivodexamethasone concentration (as nanograms of dexamethasone permilliliter of vitreous fluid) as a function of time, for: (a) a single350 μg dexamethasone implant; (b) a single 700 μg dexamethasone implant,and; (c) the three implant system of Example 1 and 3.

FIG. 3 is a graph which shows in vitro cumulative release ofdexamethasone (as a percent of the total amount of dexamethasone loadedinto each implant) as a function of time, for the multiple polymer,single implant systems of Examples 4 and 5.

FIG. 4 is a graph which shows in vitro cumulative release ofdexamethasone (as a percent of the total amount of dexamethasone loadedinto each implant) as a function of time, for additional embodiments ofthe multiple polymer, single implant system of Examples 4 and 5.

FIG. 5 is a graph which shows in a comparative fashion in vivodexamethasone concentration (as nanograms of dexamethasone permilliliter of vitreous fluid) as a function of time, for: (a) an singlepolymer (RG755) 3 mg implant loaded with 1500 μg of dexamethasone; (b) aparticular multiple polymer (R203 island and RG502H sea) 3 mg madeaccording to the method of Example 4 loaded with 1500 μg ofdexamethasone; (c) an single polymer 0.5 mg implant loaded with 350 μgof dexamethasone, and; (d) an single polymer 1 mg implant loaded with700 μg of dexamethasone.

DESCRIPTION

The present invention is based upon the discovery of bioerodibleimplants which can release a therapeutic amount of an active agent foran extended period of time to treat a posterior ocular condition. Thepresent invention encompasses biodegradable ocular implants and implantsystems and methods of using such implants and implant systems fortreating posterior ocular conditions. The implants can be formed to bemonolithic, that is the active agent is homogenously distributed ordispersed throughout the biodegradable polymer matrix. Additionally, theimplants can are formed to release an active agent into an ocular regionof the eye over various extended release time periods. Thus, the activeagent can be released from implants made according to the presentinvention for an extended periods of time of approximately 60 days ormore, 90 days or more, 120 days or more, 6 months or more, 8 months ormore or 12 months or more.

Biodegradable Implants for Treating an Ocular Condition

The implants of the present invention can include an active agent mixedwith or dispersed within a biodegradable polymer. The implantcompositions can vary according to the preferred drug release profile,the particular active agent used, the ocular condition being treated,and the medical history of the patient. Active agents that may be usedinclude, but are not limited to (either by itself in an implant withinthe scope of the present invention or in combination with another activeagent): ace-inhibitors, endogenous cytokines, agents that influencebasement membrane, agents that influence the growth of endothelialcells, adrenergic agonists or blockers, cholinergic agonists orblockers, aldose reductase inhibitors, analgesics, anesthetics,antiallergics, anti-inflammatory agents, antihypertensives, pressors,antibacterials, antivirals, antifungals, antiprotozoals,anti-infectives, antitumor agents, antimetabolites, antiangiogenicagents, tyrosine kinase inhibitors, antibiotics such as aminoglycosidessuch as gentamycin, kanamycin, neomycin, and vancomycin; amphenicolssuch as chloramphenicol; cephalosporins, such as cefazolin HCl;penicillins such as ampicillin, penicillin, carbenicillin, oxacillin,methicillin; lincosamides such as lincomycin; polypeptide antibioticssuch as polymyxin and bacitracin; tetracyclines such as tetracycline;quinolones such as ciprofloxacin, etc.; sulfonamides such as chloramineT; and sulfones such as sulfanilic acid as the hydrophilic entity,anti-viral drugs, e.g. acyclovir, gancyclovir, vidarabine,azidothymidine, dideoxyinosine, dideoxycytosine, dexamethasone,ciprofloxacin, water soluble antibiotics, such as acyclovir,gancyclovir, vidarabine, azidothymidine, dideoxyinosine,dideoxycytosine; epinephrine; isoflurophate; adriamycin; bleomycin;mitomycin; ara-C; actinomycin D; scopolamine; and the like, analgesics,such as codeine, morphine, ketorolac, naproxen, etc., an anesthetic,e.g. lidocaine; β-adrenergic blocker or β-adrenergic agonist, e.g.ephedrine, epinephrine, etc.; aldose reductase inhibitor, e.g.epalrestat, ponalrestat, sorbinil, tolrestat; antiallergic, e.g.cromolyn, beclomethasone, dexamethasone, and flunisolide; colchicine,anthelmintic agents, e.g. ivermectin and suramin sodium; antiamoebicagents, e.g. chloroquine and chlortetracycline; and antifungal agents,e.g. amphotericin, etc., anti-angiogenesis compounds such as anecortaveacetate, retinoids such as Tazarotene, anti-glaucoma agents, such asbrimonidine (Alphagan and Alphagan P), acetazolamide, bimatoprost(Lumigan), timolol, mebefunolol; memantine; alpha-2 adrenergic receptoragonists; 2-methoxyestradiol; anti-neoplastics, such as vinblastine,vincristine, interferons; alpha, beta and gamma., antimetabolites, suchas folic acid analogs, purine analogs, and pyrimidine analogs;immunosuppressants such as azathioprine, cyclosporine and mizoribine;miotic agents, such as carbachol, mydriatic agents such as atropine,etc., protease inhibitors such as aprotinin, camostat, gabexate,vasodilators such as bradykinin, etc., and various growth factors, suchepidermal growth factor, basic fibroblast growth factor, nerve growthfactors, and the like.

In one variation the active agent is methotrexate. In another variation,the active agent is a retinoic acid. In another variation, the activeagent is an anti-inflammatory agent such as a nonsteroidalanti-inflammatory agent. Nonsteroidal anti-inflammatory agents that maybe used include, but are not limited to, aspirin, diclofenac,flurbiprofen, ibuprofen, ketorolac, naproxen, and suprofen. In a furthervariation, the anti-inflammatory agent is a steroidal anti-inflammatoryagent, such as dexamethasone.

Steroidal Anti-Inflammatory Agents

The steroidal anti-inflammatory agents that may be used in the ocularimplants include, but are not limited to, 21-acetoxypregnenolone,alclometasone, algestone, amcinonide, beclomethasone, betamethasone,budesonide, chloroprednisone, clobetasol, clobetasone, clocortolone,cloprednol, corticosterone, cortisone, cortivazol, deflazacort,desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone,difluprednate, enoxolone, fluazacort, flucloronide, flumethasone,flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl,fluocortolone, fluorometholone, fluperolone acetate, fluprednideneacetate, fluprednisolone, flurandrenolide, fluticasone propionate,formocortal, halcinonide, halobetasol propionate, halometasone,halopredone acetate, hydrocortamate, hydrocortisone, loteprednoletabonate, mazipredone, medrysone, meprednisone, methylprednisolone,mometasone furoate, paramethasone, prednicarbate, prednisolone,prednisolone 25-diethylamino-acetate, prednisolone sodium phosphate,prednisone, prednival, prednylidene, rimexolone, tixocortol,triamcinolone, triamcinolone acetonide, triamcinolone benetonide,triamcinolone hexacetonide, and any of their derivatives.

In one embodiment, cortisone, dexamethasone, fluocinolone,hydrocortisone, methylprednisolone, prednisolone, prednisone, andtriamcinolone, and their derivatives, are preferred steroidalanti-inflammatory agents. In another preferred variation, the steroidalanti-inflammatory agent is dexamethasone. In another variation, thebiodegradable implant includes a combination of two or more steroidalanti-inflammatory agents.

The active agent, such as a steroidal anti-inflammatory agent, cancomprise from about 10% to about 90% by weight of the implant. In onevariation, the agent is from about 40% to about 80% by weight of theimplant. In a preferred variation, the agent comprises about 60% byweight of the implant. In a more preferred embodiment of the presentinvention, the agent can comprise about 50% by weight of the implant.

Biodegradable Polymers

In one variation, the active agent can be homogeneously dispersed in thebiodegradable polymer of the implant. The implant can be made, forexample, by a sequential or double extrusion method. The selection ofthe biodegradable polymer used can vary with the desired releasekinetics, patient tolerance, the nature of the disease to be treated,and the like. Polymer characteristics that are considered include, butare not limited to, the biocompatibility and biodegradability at thesite of implantation, compatibility with the active agent of interest,and processing temperatures. The biodegradable polymer matrix usuallycomprises at least about 10, at least about 20, at least about 30, atleast about 40, at least about 50, at least about 60, at least about 70,at least about 80, or at least about 90 weight percent of the implant.In one variation, the biodegradable polymer matrix comprises about 40%to 50% by weight of the implant.

Biodegradable polymers which can be used include, but are not limitedto, polymers made of monomers such as organic esters or ethers, whichwhen degraded result in physiologically acceptable degradation products.Anhydrides, amides, orthoesters, or the like, by themselves or incombination with other monomers, may also be used. The polymers aregenerally condensation polymers. The polymers can be crosslinked ornon-crosslinked. If crosslinked, they are usually not more than lightlycrosslinked, and are less than 5% crosslinked, usually less than 1%crosslinked.

For the most part, besides carbon and hydrogen, the polymers willinclude oxygen and nitrogen, particularly oxygen. The oxygen may bepresent as oxy, e.g., hydroxy or ether, carbonyl, e.g.,non-oxo-carbonyl, such as carboxylic acid ester, and the like. Thenitrogen can be present as amide, cyano, and amino. An exemplary list ofbiodegradable polymers that can be used are described in Heller,Biodegradable Polymers in Controlled Drug Delivery, In: “CRC CriticalReviews in Therapeutic Drug Carrier Systems”, Vol. 1. CRC Press, BocaRaton, Fla. (1987).

Of particular interest are polymers of hydroxyaliphatic carboxylicacids, either homo- or copolymers, and polysaccharides. Included amongthe polyesters of interest are homo- or copolymers of D-lactic acid,L-lactic acid, racemic lactic acid, glycolic acid, caprolactone, andcombinations thereof. Copolymers of glycolic and lactic acid are ofparticular interest, where the rate of biodegradation is controlled bythe ratio of glycolic to lactic acid. The percent of each monomer inpoly(lactic-co-glycolic)acid (PLGA) copolymer may be 0-100%, about15-85%, about 25-75%, or about 35-65%. In certain variations, 25/75 PLGAand/or 50/50 PLGA copolymers are used. In other variations, PLGAcopolymers are used in conjunction with polylactide polymers.

Biodegradable polymer matrices that include mixtures of hydrophilic andhydrophobic ended PLGA may also be employed, and are useful inmodulating polymer matrix degradation rates. Hydrophobic ended (alsoreferred to as capped or end-capped) PLGA has an ester linkagehydrophobic in nature at the polymer terminus. Typical hydrophobic endgroups include, but are not limited to alkyl esters and aromatic esters.Hydrophilic ended (also referred to as uncapped) PLGA has an end grouphydrophilic in nature at the polymer terminus PLGA with a hydrophilicend groups at the polymer terminus degrades faster than hydrophobicended PLGA because it takes up water and undergoes hydrolysis at afaster rate (Tracy et al., Biomaterials 20:1057-1062 (1999)). Examplesof suitable hydrophilic end groups that may be incorporated to enhancehydrolysis include, but are not limited to, carboxyl, hydroxyl, andpolyethylene glycol. The specific end group will typically result fromthe initiator employed in the polymerization process. For example, ifthe initiator is water or carboxylic acid, the resulting end groups willbe carboxyl and hydroxyl. Similarly, if the initiator is amonofunctional alcohol, the resulting end groups will be ester orhydroxyl.

Additional Agents

Other agents may be employed in the formulation for a variety ofpurposes. For example, buffering agents and preservatives may beemployed. Preservatives which may be used include, but are not limitedto, sodium bisulfate, sodium bisulfate, sodium thiosulfate, benzalkoniumchloride, chlorobutanol, thimerosal, phenylmercuric acetate,phenylmercuric nitrate, methylparaben, polyvinyl alcohol and phenylethylalcohol. Examples of buffering agents that may be employed include, butare not limited to, sodium carbonate, sodium borate, sodium phosphate,sodium acetate, sodium bicarbonate, and the like, as approved by the FDAfor the desired route of administration. Electrolytes such as sodiumchloride and potassium chloride may also be included in the formulation.

The biodegradable ocular implants can also include additionalhydrophilic or hydrophobic compounds that accelerate or retard releaseof the active agent. Additionally, release modulators such as thosedescribed in U.S. Pat. No. 5,869,079 can be included in the implants.The amount of release modulator employed will be dependent on thedesired release profile, the activity of the modulator, and on therelease profile of the glucocorticoid in the absence of modulator. Wherethe buffering agent or release enhancer or modulator is hydrophilic, itmay also act as a release accelerator. Hydrophilic additives act toincrease the release rates through faster dissolution of the materialsurrounding the drug particles, which increases the surface area of thedrug exposed, thereby increasing the rate of drug diffusion. Similarly,a hydrophobic buffering agent or enhancer or modulator can dissolve moreslowly, slowing the exposure of drug particles, and thereby slowing therate of drug diffusion.

Release Kinetics

An implant within the scope of the present invention can be formulatedwith particles of an active agent dispersed within a biodegradablepolymer matrix. Without being bound by theory, it is believed that therelease of the active agent can be achieved by erosion of thebiodegradable polymer matrix and by diffusion of the particulate agentinto an ocular fluid, e.g., the vitreous, with subsequent dissolution ofthe polymer matrix and release of the active agent. Factors whichinfluence the release kinetics of active agent from the implant caninclude such characteristics as the size and shape of the implant, thesize of the active agent particles, the solubility of the active agent,the ratio of active agent to polymer(s), the method of manufacture, thesurface area exposed, and the erosion rate of the polymer(s). Therelease kinetics achieved by this form of active agent release aredifferent than that achieved through formulations which release activeagents through polymer swelling, such as with crosslinked hydrogels. Inthat case, the active agent is not released through polymer erosion, butthrough polymer swelling and drug diffusion, which releases agent asliquid diffuses through the pathways exposed.

The release rate of the active agent can depend at least in part on therate of degradation of the polymer backbone component or componentsmaking up the biodegradable polymer matrix. For example, condensationpolymers may be degraded by hydrolysis (among other mechanisms) andtherefore any change in the composition of the implant that enhanceswater uptake by the implant will likely increase the rate of hydrolysis,thereby increasing the rate of polymer degradation and erosion, and thusincreasing the rate of active agent release.

The release kinetics of the implants of the present invention can bedependent in part on the surface area of the implants. A larger surfacearea exposes more polymer and active agent to ocular fluid, causingfaster erosion of the polymer matrix and dissolution of the active agentparticles in the fluid. Therefore, the size and shape of the implant mayalso be used to control the rate of release, period of treatment, andactive agent concentration at the site of implantation. At equal activeagent loads, larger implants will deliver a proportionately larger dose,but depending on the surface to mass ratio, may possess a slower releaserate. For implantation in an ocular region, the total weight of theimplant preferably ranges, e.g., from about 100 μg to about 15 mg. Morepreferably, from about 300 μg to about 10 mg, and most preferably fromabout 500 μg to about 5 mg. In a particularly preferred embodiment ofthe present invention the weight of an implant is between about 500 μgand about 2 mg, such as between about 500 μg and about 1 mg.

The bioerodible implants are typically solid, and may be formed asparticles, sheets, patches, plaques, films, discs, fibers, rods, and thelike, or may be of any size or shape compatible with the selected siteof implantation, as long as the implants have the desired releasekinetics and deliver an amount of active agent that is therapeutic forthe intended medical condition of the eye. The upper limit for theimplant size will be determined by factors such as the desired releasekinetics, toleration for the implant at the site of implantation, sizelimitations on insertion, and ease of handling. For example, thevitreous chamber is able to accommodate relatively large rod-shapedimplants, generally having diameters of about 0.05 mm to 3 mm and alength of about 0.5 to about 10 mm. In one variation, the rods havediameters of about 0.1 mm to about 1 mm. In another variation, the rodshave diameters of about 0.3 mm to about 0.75 mm. In yet a furthervariation, other implants having variable geometries but approximatelysimilar volumes may also be used.

The proportions of active agent, polymer, and any other modifiers may beempirically determined by formulating several implants with varyingproportions. A USP approved method for dissolution or release test canbe used to measure the rate of release (USP 23; NF 18 (1995) pp.1790-1798). For example, using the infinite sink method, a weighedsample of the drug delivery device is added to a measured volume of asolution containing 0.9% NaCl in water, where the solution volume willbe such that the drug concentration after release is less than 20%, andpreferably less than 5%, of saturation. The mixture is maintained at 37°C. and stirred slowly to ensure drug diffusion after bioerosion. Theappearance of the dissolved drug as a function of time may be followedby various methods known in the art, such as spectrophotometrically,HPLC, mass spectroscopy, etc.

Applications

Examples of ocular conditions which can be treated by the implants andmethods of the invention include, but are not limited to, glaucoma,uveitis, macular edema, macular degeneration, retinal detachment,posterior ocular tumors, fungal or viral infections, multifocalchoroiditis, diabetic retinopathy, proliferative vitreoretinopathy(PVR), sympathetic ophthalmia, Vogt Koyanagi-Harada (VKH) syndrome,histoplasmosis, uveal diffusion, and vascular occlusion. In onevariation, the implants are particularly useful in treating such medicalconditions as uveitis, macular edema, vascular occlusive conditions,proliferative vitreoretinopathy (PVR), and various other retinopathies.

Methods of Implantation

The biodegradable implants can be inserted into the eye by a variety ofmethods, including placement by forceps, by trocar, or by other types ofapplicators, after making an incision in the sclera. In some instances,a trocar or applicator may be used without creating an incision. In apreferred variation, a hand held applicator is used to insert one ormore biodegradable implants into the eye. The hand held applicatortypically comprises an 18-30 GA stainless steel needle, a lever, anactuator, and a plunger. Suitable devices for inserting an implant orimplants into a posterior ocular region or site includes those disclosedin U.S. patent application Ser. No. 10/666,872.

The method of implantation generally first involves accessing the targetarea within the ocular region with the needle, trocar or implantationdevice. Once within the target area, e.g., the vitreous cavity, a leveron a hand held device can be depressed to cause an actuator to drive aplunger forward. As the plunger moves forward, it can push the implantor implants into the target area (i.e. the vitreous).

Methods for Making Implants

Various techniques may be employed to make implants within the scope ofthe present invention. Useful techniques include phase separationmethods, interfacial methods, extrusion methods, compression methods,molding methods, injection molding methods, heat press methods and thelike.

Choice of the technique, and manipulation of the technique parametersemployed to produce the implants can influence the release rates of thedrug. Room temperature compression methods result in an implant withdiscrete microparticles of drug and polymer interspersed. Extrusionmethods result in implants with a progressively more homogenousdispersion of the drug within a continuous polymer matrix, as theproduction temperature is increased.

The use of extrusion methods allows for large-scale manufacture ofimplants and results in implants with a homogeneous dispersion of thedrug within the polymer matrix. When using extrusion methods, thepolymers and active agents that are chosen are stable at temperaturesrequired for manufacturing, usually at least about 50° C. Extrusionmethods use temperatures of about 25° C. to about 150° C., morepreferably about 60° C. to about 130° C.

Different extrusion methods may yield implants with differentcharacteristics, including but not limited to the homogeneity of thedispersion of the active agent within the polymer matrix. For example,using a piston extruder, a single screw extruder, and a twin screwextruder will generally produce implants with progressively morehomogeneous dispersion of the active. When using one extrusion method,extrusion parameters such as temperature, extrusion speed, die geometry,and die surface finish will have an effect on the release profile of theimplants produced.

In one variation of producing implants by a piston extrusion methods,the drug and polymer are first mixed at room temperature and then heatedto a temperature range of about 60° C. to about 150° C., more usually toabout 100° C. for a time period of about 0 to about 1 hour, more usuallyfrom about 0 to about 30 minutes, more usually still from about 5minutes to about 15 minutes, and most usually for about 10 minutes. Theimplants are then extruded at a temperature of about 60° C. to about130° C., preferably at a temperature of about 90° C.

In an exemplary screw extrusion method, the powder blend of active agentand polymer is added to a single or twin screw extruder preset at atemperature of about 80° C. to about 130° C., and directly extruded as afilament or rod with minimal residence time in the extruder. Theextruded filament or rod is then cut into small implants having theloading dose of active agent appropriate to treat the medical conditionof its intended use.

Implant systems according to the invention can include a combination ofa number of bioerodible implants, each having unique polymercompositions and drug release profiles that when co-administered providefor an extended continuous release of drug. Further, the achievedcontinuous release of drug is both prolonged and distinct from therelease profile that would occur with a single implant consisting of ablend of the polymers. For example, to achieve continuous release of atleast 120 days, three individual implants made of separate polymers thathave fast, medium and slow release characteristics can be employed, withthe fast release implant releasing most of the drug from 0-60 days, themedium release implant releasing most of the drug from 60-100 days, andthe slow release implant releasing most of the drug from 100 days on.Examples of fast release implants include those made of certain lowermolecular weight, fast degradation profile polylactide polymers, such asR104 made by Boehringer Ingelheim GmbH, Germany, which is apoly(D,L-lactide) with a molecular weight of about 3,500. Examples ofmedium release implants include those made of certain medium molecularweight, intermediate degradation profile PLGA co-polymers, such as RG755made by Boehringer Ingelheim GmbH, Germany, which is apoly(D,L-lactide-co-glycolide with wt/wt 75% lactide:25% glycolide, amolecular weight of about 40,000 and an inherent viscosity of 0.50 to0.70 dl/g. Examples of slow release implants include those made ofcertain other high molecular weight, slower degradation profilepolylactide polymers, such as R203/RG755 made by Boehringer IngelheimGmbH, Germany, for which the molecular weight is about 14,000 for 8203(inherent viscosity of 0.25 to 0.35 dl/g) and about 40,000 for RG755.When administered together, these implants provide for an extendcontinuous release of drug over a period of at least 120 days in vitrowhich can result in sustained drug levels (concentration) of at leastabout 5-10 ng dexamethasone equivalent/mL in the vitreous (i.e. in vivo)for up to about 240 days.

Single bioerodible implants with extended release profiles can also beprepared according to the invention using two or more differentbioerodible polymers each having different release characteristics. Inone such method, particles of a drug or active agent are blended with afirst polymer and extruded to form a filament or rod. This filament orrod is then itself broken first into small pieces and then furtherground into particles with a size (diameter) between about 30 μm andabout 50 μm. which are then blended with an additional quantities of thedrug or active agent and a second polymer. This second mixture is thenextruded into filaments or rods which are then cut to the appropriatesize to form the final implant. The resultant implant has a releaseprofile different than that of an implant created by initially blendingthe two polymers together and then extruding it. It is posited thatformed implant includes initial particles of the drug and first polymerhaving certain specific release characteristics bound up in the secondpolymer and drug blend that itself has specific release characteristicsthat are distinct from the first. Examples of implants include thoseformed with RG755, 8203, RG503, RG502, RG 502H as the first polymer, andRG502, RG 502H as the second polymer. Other polymers that can be usedinclude PDL (poly(D,L-lactide)) and PDLG(poly(D,L-lactide-co-glycolide)) polymers available from PURAC America,Inc. Lincolnshire, Ill. Poly(caprolactone) polymers can also be used.The characteristics of the specified polymers are (1) RG755 has amolecular weight of about 40,000, a lactide content (by weight) of 75%,and a glycolide content (by weight) of 25%; (2) 8203 has a molecularweight of about 14,000, and a lactide content of 100%; (3) RG503 has amolecular weight of about 28,000, a lactide content of 50%, and aglycolide content of 50%; (4) RG502 has a molecular weight of about11,700 (inherent viscosity of 0.16 to 0.24 dl/g), a lactide content of50%, and a glycolide content of 50%, and; (5) RG502H has a molecularweight of about 8,500, a lactide content of 50%, a glycolide content of50% and free acid at the end of polymer chain.

Generally, if inherent viscosity is 0.16 the molecular weight is about6,300, and if the inherent viscosity is 0.28 the molecular weight isabout 20,700. It is important to note that all polymer molecular weightsset forth herein are averaged molecular weights in Daltons.

According to our invention continual or substantially continual releaseof drug at levels corresponding to at least 10 ng/ml of dexamethasone ordexamethasone equivalent for at least 60 days can be achieved.

In other methods, single implants can be made using polymers withdiffering release characteristics where separate drug-polymer blends areprepared that are then co-extruded to create implants that containdifferent areas or regions having different release profiles. Theoverall drug release profile of these co-extruded implants are differentthan that of an implant created by initially blending the polymerstogether and then extruding them. For example, first and second blendsof drug or active agent can be created with different polymers and thetwo blends can be co-axially extruded to create an implant with an innercore region having certain release characteristics and an outer shellregion having second, differing release characteristics.

EXAMPLES

The following examples illustrate aspects and embodiments of theinvention.

Example 1 Preparation of Dexamethasone Three Implant Extended ReleaseSystem

A bioerodible implant system for extended delivery of dexamethasone wasmade by mixing the active agent dexamethasone (Pharmacia Corp., Peapack,N.J.) separately with each of the following three different polymers:

1. poly (D,L-lactide) (R104, Boehringer Ingelheim GmbH, Germany),

2. poly(D,L-lactide-co-glycolide) as a 75:25 (wt %/wt %) blend oflactide:glycolide (RG755, Boehringer Ingelheim GmbH, Germany), and;

3. poly (D,L-lactide) (R203, Boehringer Ingelheim GmbH, Germany), so asto obtain three different dexamethasone-polymer mixes.

R203 and R104 both are poly(D,L-lactide) polymers, but with differentmolecular weights. The molecular weight for 8203 is about 14,000, whilethe molecular weight for R104 is about 3,500. RG755 is apoly(lactide-co-glycolide) co-polymer. The molecular weight of RG755 isabout 40,000.

The dexamethasone and one of the three polymers specified above werethoroughly mixed at a ratio of 50/50 by weight ratio of dexamethasoneand each of the three polymers.

Each of the three separate batches of the three dexamethasone-polymerblends were then fed into a single-piston thermal extruder and threedifferent extruded dexamethasone-polymer filaments were thereby made.The filaments were further processed to obtain individual segments(implants), each segment being about a 1 mg implant containingapproximately 0.5 mg of dexamethasone. The three implant systemconsisted of one of each of the 1 mg implants for each of the threepolymers (R104, RG755 or 8203) which had been combined separately with0.5 mg of dexamethasone). The total dexamethasone concentration in thecombined three implants was about 1.5 mg, as of the three implantsweighed about 1 mg and each of the three implants contained about 50% byweight dexamethasone. A three implant dexamethasone extended releasesystem was thereby made.

Example 2 In Vitro Release of Dexamethasone from Three Implant ExtendedRelease System

Cumulative release of dexamethasone from the three implant system ofExample 1 was measured in vitro. The three implant system was placed ina glass vial filled with receptor medium (0.1 M phosphate solution, pH4.4, at 37 degrees C.). To allow for “infinite sink” conditions, thereceptor medium volume was chosen so that the concentration would neverexceed 5% of saturation. To minimize secondary transport phenomena, e.g.concentration polarization in the stagnant boundary layer, the glassvial was placed into a shaking water bath at 37° C. Samples were takenfor HPLC analysis from the vial at defined time points. Theconcentration values were used to calculate the cumulative release data,as shown in Table 1 and the corresponding FIG. 1. In Table 1 “Day” isthe day of the in vitro measurement of the cumulative amount ofdexamethasone released from the three implants, “Cum.” is anabbreviation for cumulative and “Dex” is an abbreviation fordexamethasone.

FIG. 1B is a graph which shows the same in vitro cumulative release ofdexamethasone shown by FIG. 1, and shows as well the in vitro cumulativerelease of dexamethasone from each of the three separate (control)polymers release separately from each of the 1 mg implants for each ofthe three polymers (R104, RG755 or 8203) which had been combinedseparately with 0.5 mg of dexamethasone. Table 1B sets forth the datafor FIG. 1B.

This experiment showed that use of the cumulative release ofdexamethasone from the three implant system of Example 1 permitted invitro release over a 161 day period, a substantially continuous releaseof the active agent at a substantially constant release rate (i.e.approximately linear, positive slope).

Example 3 In Vivo Release of Dexamethasone from Three Implant ExtendedRelease System

The three implant system of Example 1 was implanted into the vitreous ofthe eyes of eight rabbits. This was carried out by loading the threeimplants of Example 1 into a simple trocar with a sample holder andplunger, making an incision through the lower front sclera, insertingthe trocar through the scleral incision, and depressing the trocarplunger to deposit the three implants of Example 1 into the vitreous.The in vivo vitreous concentrations of dexamethasone were monitored byvitreous sampling, using LC/MS (liquid chromatography and massspectrometry). The dexamethasone concentrations for each eye weremeasured at days 7, 30, 60, 90, 120, 150, 180, 210 and 240 and 360 forthe three implant system of Example 1. The averaged results of one mixedconcentration measurement are set forth by the two left hand sidecolumns of Table 2.

Comparison studies were also carried out using single (Posurdex)implants of dexamethasone and a bioerodible PLGA polymer. Specifically,the single extruded comparison study implants were formed ofdexamethasone mixed with polylactic acid-polyglycolic acid (PLGA) as thebiodegradable polymer at a ratio of 60/30/10 by weight of dexamethasone(60% by weight), PLGA (RG502, Boehringer Ingelheim GmbH, Germany) (10%by weight), and free acid end PLGA (RG502H, Boehringer Ingelheim GmbH,Germany) (30% by weight), respectively. Two versions of these comparisonstudy implants were prepared; one contained 350 μg of dexamethasone andthe other implant contained 700 μg of dexamethasone. These singlebioerodible dexamethasone (Posurdex) implants were in the same mannerused for the three implant systems implanted into the vitreous of rabbiteyes (note that only one of either the 350 μg dexamethasone or the 700μg dexamethasone bioerodible implant was placed into each eye) and invivo vitreous concentrations of dexamethasone from the 350 μg and 700 μgcomparison study single implants were monitored by vitreous sampling.The dexamethasone concentrations for each eye were measured at days 1,4, 7, 14, 21, 28, 35, 42; as shown as the three right hand side columnsof by Table 2.

The RG502 (molecular weight is about 11,700) and RG502H (molecularweight is about 8,500) polymers used are bothpoly(D,L-lactide-co-glycolide). RG502H has a free acid at the end of itspolymer chain.

All dexamethasone measurement are as concentrations in ng dexamethasoneper ml of vitreous fluid.

FIG. 2 shows (using the Table 2 data) the vitreous concentrations ofdexamethasone assayed after different time periods after intra-vitrealin vivo implantation of the implant system of Example 1 in comparison tothe vitreous concentrations of dexamethasone obtained for the singleintra-vitreal implantation of the 350 μg or 700 μg dexamethasoneimplants described above in this Example 3.

This experiment showed that the bioerodible implant system of Example 1can release dexamethasone in vivo into the vitreous: (1) for a timeperiod both much longer than (i.e. about 360 days vs about 30 days) andin a much more linear fashion than can a single dexamethasone agent(comparison study) implant. Significantly, this experiment showed thatuse of three bioerodible polymeric dexamethasone implants wherein eachof the implant polymers was different permitted (as a cumulative view ofthe release characteristics of the three implants taken together), invivo over a 360 day period, a substantially continuous release of thedexamethasone active agent at a substantially constant release rate(i.e. approximately linear release with substantially zero slope).

Additionally, this experiment showed that the bioerodible implant systemof Example 1 can release and maintain an in vivo in the vitreous adexamethasone (or dexamethasone equivalent) concentration of at least 10ng/ml or of at least about 100 ng/ml for a period of time of 120 days orfor 360 days. This experiment also showed that by comparison, the single(350 or 700 μg) implants exhausted delivery of dexamethasone into thevitreous after about 30 days and that even during that more shorterrelease period the single bioerodible implant could not release ormaintain an in vivo in the vitreous a dexamethasone (or dexamethasoneequivalent) concentration with either a substantially continuous releaseor with a substantially constant release rate of the active agent.

Example 4 Preparation of Dexamethasone Extended Delivery Single Implants

A. Extended delivery implants containing dexamethasone were prepared asfollows. The active agent dexamethasone was first thoroughly mixed witha selected polymer at a ratio of 60% by weight dexamethasone and 40% byweight polymer in five separate batches with each of the following fivedifferent bioerodible polymers:

1. poly (D,L-lactide) (R203, Boehringer Ingelheim GmbH, Germany),

2. poly (D,L-lactide-co-glycolide) (PLGA) at 50% lactide/%50 glycolicacid (50/50) (R502, Boehringer Ingelheim GmbH, Germany),

3. PLGA free acid end (50/50) (RG502H, Boehringer Ingelheim GmbH,Germany),

4. PLGA 50/50 (R503, Boehringer Ingelheim GmbH, Germany), and;

5. PLGA 75% lactide/25% glycolic acid (RG755, Boehringer Ingelheim GmbH,Germany).

B. RG755: molecular weight is about 40,000; lactide is 75% by weight andglycolide is 25% by weight.

-   R203: molecular weight is about 14,000, lactide=100%-   RG503: molecular weight is about 28,300, lactide=50%, glycolide=50%-   RG502: molecular weight is about 11,700, lactide=50%, glycolide=50%-   RG502H: molecular weight is about 8,500, lactide=50%, glycolide=50%,    free acid at the end of polymer chain.

C. The dexamethasone active agent and the polymer (one of the five) werethoroughly mixed at a ratio of 60/40 (wt/wt) by weight of dexamethasoneand polymer for each batch. This was carried out with each of the fivepolymers to obtain five different dexamethasone-polymer blends (sameamount of dexamethasone in each of the five different polymer blends).

D. Each of the five separate batches of the five different 60%dexamethasone-40% polymer blends were then fed separately into anextruder and five different extruded dexamethasone-polymer filamentswere collected. The filaments so obtained were then separately groundinto dexamethasone-polymer particles of 30 μm to 50 μm in diameter.There was thereby prepared five different “islands”, as explained below.

E. There was then separately prepared: (1) a blend of dexamethasone andRG502 polymer (as dexamethasone 40% by weight/RG502 60% by weight), and;(2) a blend of dexamethasone and RG502H polymer (as dexamethasone 40% byweight/RG502H 60% by weight). There was thereby prepared two different“seas”, as explained below.

F. For each of the five batches of the dexamethasone-polymer (one offive) particles (the islands) previously obtained, the particles werethen separately and thoroughly mixed with either thedexamethasone-bioerodible polymer RG502 blend or with thedexamethasone-bioerodible polymer RG502H blend (i.e. with one of theseas). The resulting (island and sea) mixture was then again fed into anextruder and the extruded dexamethasone-polymer filaments were collectedand further processed to obtain individual segments, each providing asingle, composite implant comprising 500 μg of dexamethasone.

In summary, the 500 μg dexamethasone first extruded filament (60/40dexamethasone/polymer) was ground into particles and the particles mixedwith the 500 μg second batch (which was 40/60 dexamethasone/polymer) sothe amount of dexamethasone in the final 1 mg extruded filament: was(500 μg×60%)+(500 μg×40%)=500 μg dexamethasone.

G. The word “island” is used here to mean the dexamethasone-bioerodiblepolymer particle prepared in paragraph D. above. The word “sea” is usedto describe dexamethasone dispersed (such as homogenously dispersed)within a second bioerodible polymer (i.e. not as particles or islands),as set forth by paragraph E. above.

Three control implants were also prepared. All three control implantswere all sea implants (no islands). The first control implant consistedof dexamethasone dispersed within the bioerodible polymer RG502H. Thesecond control implant consisted of dexamethasone dispersed within thebioerodible polymer RG502. The third control implant consisted ofdexamethasone dispersed within the bioerodible polymer R203.

All the control implants were made by extruding a single polymer anddexamethasone mixture. The three control implants were essentiallyPosurdex type implants. All the control group samples were prepared by50/50% weight of dexamethasone and individual polymer, and were preparedas a 1 mg implant containing 500 μg dexamethasone).

Each of these two island and sea implants and each of the three controlimplants contained 500 μg of dexamethasone.

The implants set forth above in Example 4 were made as 1 mg cylindricalimplants. Also made, by tripling the polymer and dexamethasone amountsset forth above, were 3 mg (1500 μg of dexamethasone) RG755 singlepolymer implants, and 3 mg (1500 μg dexamethasone) R203/RG502H twopolymer implants.

Example 5 In Vitro Performance of Dexamethasone Extended Delivery SingleImplants

Release of dexamethasone from selected implants of Example 4 wasmeasured in vitro. Control implants were also prepared and tested, thecontrol implants made by extruding a single polymer and dexamethasonemixture. In all control groups, the samples were prepared by 50/50%weight of dexamethasone and individual polymer, and there was 500 μgdexamethasone per each 1 mg implant. Implants were placed in glass vialsfilled with receptor medium (0.1 M phosphate solution, pH 4.4, at 37degrees C.). To allow for “infinite sink” conditions, the receptormedium volume was chosen so that the concentration would never exceed 5%of saturation. To minimize secondary transport phenomena, e.g.concentration polarization in the stagnant boundary layer, the glassvials were placed into a shaking water bath at 37° C. Samples were takenfor HPLC analysis from the vials at days 1, 4, 7, 14, 21, 28, 35, 42 and49 days. Some samples were also taken on days 63 and 77. Theconcentration values were used to calculate the cumulative release data,as shown in Table 3 and FIGS. 3 and 4.

FIG. 3 presents in vitro dexamethasone release characteristic for twoimplants: (1) one where the island of the implant consisted ofdexamethasone-R203 polymer particles and the sea of the same implantconsisted of dexamethasone dispersed in RG502H polymer, and; (2) asecond implant where the island of this second implant consisted ofdexamethasone-R203 polymer particles and the sea of this second implantconsisted of dexamethasone dispersed in RG502 polymer material. It wasobserved that such island and sea implant formulations led to releaseprofiles not predictable from the individual characteristics of eitherthe island or sea bioerodible polymers alone with dexamethasone.

FIG. 4 presents in vitro dexamethasone release characteristic for twoimplants: (1) one where the island of the implant consisted ofdexamethasone-RG755 polymer particles and the sea of the same implantconsisted of dexamethasone dispersed in RG502H polymer, and; (2) asecond implant where the island of this second implant consisted ofdexamethasone-RG755 polymer particles and the sea of this second implantconsisted of dexamethasone dispersed in RG502 polymer material. It wasobserved that such island and sea implant formulations led to releaseprofiles not predictable from the individual characteristics of eitherthe island or sea bioerodible polymers alone with dexamethasone.

These in vitro release results show that implants made from a pluralityof polymers can have varying in vitro release profiles which permitsubstantially linear release of dexamethasone for up to at least about80 days.

Example 6 In Vivo Release of Dexamethasone from Extended ReleaseImplants

Implants of Example 4 were implanted into the vitreous of separate eyesof fourteen rabbits. This was carried out by loading the implant into atrocar, making an incision through the sclera, inserting the trocarthrough the scleral incision, and depressing the trocar plunger todeposit separate Example 5 into the vitreous of separate eyes. The invivo vitreous concentrations of dexamethasone were monitored by vitreoussampling using LC/MS. The dexamethasone concentrations for each eye weremeasured at days 7, 21, 35, 49, 63, 77 and 112. The averaged results ofmeasurements are set forth by Table 4 for an RG755 polymer 3 mg (1500 μgdexamethasone) implant and for a R203 (island)/RG502H (sea) 3 mg (1500μg dexamethasone) implant.

Comparison studies were also carried out using single (Posurdex) 0.5 mgor 1 mg implants of (350 μg or 700 μg) dexamethasone and a bioerodiblepolymer (“Single Polymer Implants” in Table 4) Specifically, the singleextruded process implants were formed of dexamethasone mixed withpolylactic acid-polyglycolic acid (PLGA) as the biodegradable polymer ata ratio of 70/30 by weight of dexamethasone (70% by weight), and PLGA(Birmingham Polymers, Inc., Birmingham, Ala., inherent viscosity 0.16)(30% by weight). Two versions of the implants were prepared, onecontained 350 μg of dexamethasone and the other implant contained 700 μgof dexamethasone. These single bioerodible dexamethasone (Posurdex)implants were in the same manner implanted into the vitreous of rabbiteyes (note that only one of either the 350 μg dexamethasone or the 700μg dexamethasone bioerodible implant was placed in each eye) and in vivovitreous concentrations of dexamethasone were monitored by vitreoussampling. The dexamethasone concentrations for each eye were measured atdays 1, 4, 7, 14, 21, 28, 35, 42; as also shown by Table 4. Thedexamethasone concentrations assayed (as ng dexamethasone per ml ofvitreous) are set forth in Table 4 to the right of the “Day” columns.

FIG. 5 shows (using the Table 4 data) the concentrations obtained(amount of dexamethasone assayed after different time periods afterintra-vitreal in vivo implantation of the implant system of Example 6 incomparison to the release profiles obtained for the single intra-vitrealimplantation of a 350 μg or 700 μg dexamethasone implant.

This experiment showed that particular island and sea bioerodibleimplants of Example 5 can release dexamethasone in vivo into thevitreous: (1) for a time period both much longer than (i.e. at leastabout 112 days vs about 30 days) and in a much more linear fashion thancan a single polymer active agent implant. Significantly, thisexperiment showed that the island and sea implant permitted (as acumulative view of the release characteristics of the three implantstaken together), in vivo over a 360 ay period, a substantiallycontinuous release of the active agent at a substantially constantrelease rate (i.e. approximately linear release with substantially zeroslope).

Significantly, as shown by Table 4 and FIG. 5, the single polymer RG7553 mg implant (1500 μg dexamethasone) presented an extended releaseprofile, thereby showing that a 75:25 (% by weight) lactide: glycolidesingle polymer with an inherent viscosity of about 0.50 to about 0.70dl/g can be suitable for making an extended release implant.

Additionally, this experiment showed that the bioerodible implant systemof Example 5 can release and maintain an in vivo in the vitreous adexamethasone (or dexamethasone equivalent) concentration of at least 10ng/ml or of at least about 100 ng/ml for a period of time of 120 days orfor 360 days. This experiment also showed that by comparison, the singleimplants (350 μg or 700 μg of dexamethasone) exhausted delivery ofdexamethasone into the vitreous after about 30 days and that even duringthat more shorter release period the single polymer bioerodible implantcould not release or maintain a in vivo in the vitreous a dexamethasone(or dexamethasone equivalent) concentration with either a substantiallycontinuous release or with a substantially constant release rate of theactive agent.

Example 7 Treatment of an Ocular Condition with an Anti-InflammatoryActive Agent Extended Release System

An extended release implant system can be used to treat an ocularcondition. The implant can contain a steroid, such an anti-inflammatorysteroid, such as dexamethasone as the active agent. Alternately or inaddition, the active agent can be a non-steroidal anti-inflammatory,such as ketorolac (available from Allergan, Irvine, Calif. as ketorolactromethamine ophthalmic solution, under the tradename Acular). Thus, forexample, a dexamethasone or ketorolac extended release implant system ofExample 1 or of Example 4 can be implanted into an ocular region or site(i.e. into the vitreous) of a patient with an ocular condition for adesired therapeutic effect. The ocular condition can be an inflammatorycondition such as uveitis or the patient can be afflicted with one ormore of the following afflictions: macular degeneration (includingnon-exudative age related macular degeneration and exudative age relatedmacular degeneration); choroidal neovascularization; acute macularneuroretinopathy; macular edema (including cystoid macular edema anddiabetic macular edema); Behcet's disease, diabetic retinopathy(including proliferative diabetic retinopathy); retinal arterialocclusive disease; central retinal vein occlusion; uveitic retinaldisease; retinal detachment; retinopathy; an epiretinal membranedisorder; branch retinal vein occlusion; anterior ischemic opticneuropathy; non-retinopathy diabetic retinal dysfunction, retinitispigmentosa and glaucoma. The implant(s) can be inserted into thevitreous using the procedure (trocar implantation) set forth in Example2 and 6. The implant(s) can release a therapeutic amount of, for examplethe dexamethasone or the ketorolac for an extended period of time tothereby treat a symptom of the ocular condition.

Example 8 Preparation and Therapeutic Use of an Anti-AngiogenesisExtended Release Implant(s)

An implant to treat an ocular condition according to the presentinvention can contain a steroid, such an anti-angiogenesis steroid, suchas an anecortave, as the active agent. Thus, a bioerodible implantsystem for extended delivery of anecortave acetate (an angiostaticsteroid) can be made using the method of Example 1 or the method ofExample 4, but with use of anecortave acetate as the active agent,instead of dexamethasone. The implant or implants can be loaded with atotal of about 15 mg of the anecortave (i.e. 5 mg of anecortave can beloaded into each of the three implants prepared according to the Example1 method.

The anecortave acetate extended release implant system can be implantedinto an ocular region or site (i.e. into the vitreous) of a patient withan ocular condition for a desired therapeutic effect. The ocularcondition can be an angiogenic condition or an inflammatory conditionsuch as uveitis or the patient can be afflicted with one or more of thefollowing afflictions: macular degeneration (including non-exudative agerelated macular degeneration and exudative age related maculardegeneration); choroidal neovascularization; acute macularneuroretinopathy; macular edema (including cystoid macular edema anddiabetic macular edema); Behcet's disease, diabetic retinopathy(including proliferative diabetic retinopathy); retinal arterialocclusive disease; central retinal vein occlusion; uveitic retinaldisease; retinal detachment; retinopathy; an epiretinal membranedisorder; branch retinal vein occlusion; anterior ischemic opticneuropathy; non-retinopathy diabetic retinal dysfunction, retinitispigmentosa and glaucoma. The implant(s) can be inserted into thevitreous using the procedure (trocar implantation) set forth in Example2 and 6. The implant(s) can release a therapeutic amount of theanecortave for an extended period of time to thereby treat a symptom ofthe ocular condition.

Example 9 Preparation and Therapeutic Use of an Anti-VEGF ExtendedRelease Implant(s)

VEGF (Vascular Endothelial Growth Factor) (also known as VEGF-A) is agrowth factor which can stimulate vascular endothelial cell growth,survival, and proliferation. VEGF is believed to play a central role inthe development of new blood vessels (angiogenesis) and the survival ofimmature blood vessels (vascular maintenance). Tumor expression of VEGFcan lead to the development and maintenance of a vascular network, whichpromotes tumor growth and metastasis. Thus, increased VEGF expressioncorrelates with poor prognosis in many tumor types. Inhibition of VEGFcan be an anticancer therapy used alone or to complement currenttherapeutic modalities (eg, radiation, chemotherapy, targeted biologictherapies).

VEGF is believed to exert its effects by binding to and activating twostructurally related membrane receptor tyrosine kinases, VEGF receptor-1(VEGFR-1 or flt-1) and VEGFR-2 (flk-1 or KDR), which are expressed byendothelial cells within the blood vessel wall. VEGF may also interactwith the structurally distinct receptor neuropilin-1. Binding of VEGF tothese receptors initiates a signaling cascade, resulting in effects ongene expression and cell survival, proliferation, and migration. VEGF isa member of a family of structurally related proteins (see Table Abelow). These proteins bind to a family of VEGFRs (VEGF receptors),thereby stimulating various biologic processes. Placental growth factor(PlGF) and VEGF-B bind primarily to VEGFR-1. PlGF modulates angiogenesisand may also play a role in the inflammatory response. VEGF-C and VEGF-Dbind primarily to VEGFR-3 and stimulate lymphangiogenesis rather thanangiogenesis.

TABLE A VEGF Family Members Receptors Functions VEGF (VEGF-A) VEGFR-1,VEGFR-2, Angiogenesis Vascular neuropilin-1 maintenance VEGF-B VEGFR-1Not established VEGF-C VEGF-R, VEGFR-3 Lymphangiogenesis VEGF-D VEGFR-2,VEGFR-3 Lymphangiogenesis VEGF-E (viral factor) VEGFR-2 AngiogenesisPIGF VEGFR-1, neuropilin-1 Angiogenesis and inflammation

An extended release bioerodible implant system can be used to treat anocular condition mediated by a VEGF. Thus, the implant can contain asactive agent a compound with acts to inhibit formation of VEGF or toinhibit the binding of VEGF to its VEGFR. The active agent can be, forexample, ranibizumab (rhuFab V2) (Genentech, South San Francisco,Calif.) and the implant(s) an be made using the method of Example 1 orthe method of Example 4, but with use of ranibizumab as the activeagent, instead of dexamethasone. Ranibizumab is an anti-VEGF (vascularendothelial growth factor) product which may have particular utility forpatients with macular degeneration, including the wet form ofage-related macular degeneration. The implant or implants can be loadedwith a total of about 300-500 μg of the ranibizumab (i.e. about 150 μgof ranibizumab can be loaded into each of the three implants preparedaccording to the Example 1 method.

The ranibizumab extended release implant system can be implanted into anocular region or site (i.e. into the vitreous) of a patient with anocular condition for a desired therapeutic effect. The ocular conditioncan be an inflammatory condition such as uveitis or the patient can beafflicted with one or more of the following afflictions: maculardegeneration (including non-exudative age related macular degenerationand exudative age related macular degeneration); choroidalneovascularization; acute macular neuroretinopathy; macular edema(including cystoid macular edema and diabetic macular edema); Behcet'sdisease, diabetic retinopathy (including proliferative diabeticretinopathy); retinal arterial occlusive disease; central retinal veinocclusion; uveitic retinal disease; retinal detachment; retinopathy; anepiretinal membrane disorder; branch retinal vein occlusion; anteriorischemic optic neuropathy; non-retinopathy diabetic retinal dysfunction,retinitis pigmentosa and glaucoma. The implant(s) can be inserted intothe vitreous using the procedure (trocar implantation) set forth inExample 2 and 6. The implant(s) can release a therapeutic amount of theranibizumab for an extended period of time to thereby treat a symptom ofthe ocular condition.

Pegaptanib is an aptamer that can selectively bind to and neutralizeVEGF and may have utility for treatment of, for example, age-relatedmacular degeneration and diabetic macular edema by inhibiting abnormalblood vessel growth and by stabilizing or reverse blood vessel leakagein the back of the eye resulting in improved vision. A bioerodibleimplant system for extended delivery of pegaptanib sodium (Macugen;Pfizer Inc, New York or Eyetech Pharmaceuticals, New York) can also bemade using the method of Example 1 or the method of Example 4, but withuse of pegaptanib sodium as the active agent, instead of dexamethasone.The implant or implants can be loaded with a total of about 1 mg to 3 mgof Macugen according to the Example 1 method.

The pegaptanib sodium extended release implant system can be implantedinto an ocular region or site (i.e. into the vitreous) of a patient withan ocular condition for a desired therapeutic effect.

An extended release bioerodible intraocular implant for treating anocular condition, such as an ocular tumor can also be made as set forthin this Example 9, using about 1-3 mg of the VEGF Trap compoundavailable from Regeneron, Tarrytown, new York.

Example 10 Preparation and Therapeutic Use of Beta Blocker ExtendedRelease Implant(s)

An extended release implant system to treat an ocular condition cancontain a beta-adrenergic receptor antagonist (i.e. a “beta blocker”)such as levobunolol, betaxolol, carteolol, timolol hemihydrate andtimolol. Timolol maleate is commonly used to treat of open-angleglaucoma. Thus, an extended release bioerodible implant systemcontaining timolol maleate (available from multiple different suppliersunder the trade names Timoptic, Timopol or Loptomit) as the active agentcan be made using the method of Example 1 or the method of Example 4,but with use of timolol maleate instead of dexamethasone. Thus, about 50μg to 150 μg of the timolol maleate can be loaded into each of the threeimplants prepared according to the Example 1 method.

The timolol extended release implant system can be implanted into anocular region or site (i.e. into the vitreous) of a patient with anocular condition for a desired therapeutic effect. The ocular conditioncan be an inflammatory condition such as uveitis or the patient can beafflicted with one or more of the following afflictions: maculardegeneration (including non-exudative age related macular degenerationand exudative age related macular degeneration); choroidalneovascularization; acute macular neuroretinopathy; macular edema(including cystoid macular edema and diabetic macular edema); Behcet'sdisease, diabetic retinopathy (including proliferative diabeticretinopathy); retinal arterial occlusive disease; central retinal veinocclusion; uveitic retinal disease; retinal detachment; retinopathy; anepiretinal membrane disorder; branch retinal vein occlusion; anteriorischemic optic neuropathy; non-retinopathy diabetic retinal dysfunction,retinitis pigmentosa and glaucoma. The implant(s) can be inserted intothe vitreous using the procedure (trocar implantation) set forth inExample 2 and 6. The implant(s) can release a therapeutic amount of thetimolol for an extended period of time to thereby treat a symptom of theocular condition by, for example, causing an intra-ocular pressuredepression.

Example 11 Preparation and Therapeutic Use of Prostamide ExtendedRelease Implant(s)

An extended release implant system can be used to treat an ocularcondition can contain a prostamide. Prostamides are naturally occurringsubstances biosynthesized from anandamide in a pathway that includesCOX2. Bimatoprost (Lumigan) is a synthetic prostamide analog chemicallyrelated to prostamide F. Lumigan has been approved by the FDA for thereduction of elevated intraocular pressure (TOP) in patients withopen-angle glaucoma or ocular hypertension who are intolerant of orinsufficiently responsive to other IOP-lowering medications. Lumigan isbelieved to lower intraocular pressure by increasing the outflow ofaqueous humor.

Thus, an extended release bioerodible implant system containing Lumigan(Allergan, Irvine, Calif.) as the active agent can be made using themethod of Example 1 or the method of Example 4, but with use of timololmaleate instead of dexamethasone. Thus, about 100 μg to 300 μg ofLumigan can be loaded into each of the three implants prepared accordingto the Example 1 method.

The Lumigan extended release implant system can be implanted into anocular region or site (i.e. into the vitreous) of a patient with anocular condition for a desired therapeutic effect. The ocular conditioncan be an inflammatory condition such as uveitis or the patient can beafflicted with one or more of the following afflictions: maculardegeneration (including non-exudative age related macular degenerationand exudative age related macular degeneration); choroidalneovascularization; acute macular neuroretinopathy; macular edema(including cystoid macular edema and diabetic macular edema); Behcet'sdisease, diabetic retinopathy (including proliferative diabeticretinopathy); retinal arterial occlusive disease; central retinal veinocclusion; uveitic retinal disease; retinal detachment; retinopathy; anepiretinal membrane disorder; branch retinal vein occlusion; anteriorischemic optic neuropathy; non-retinopathy diabetic retinal dysfunction,retinitis pigmentosa and glaucoma. The implant(s) can be inserted intothe vitreous using the procedure (trocar implantation) set forth inExample 2 and 6. The implant(s) can release a therapeutic amount of theLumigan for an extended period of time to thereby treat a symptom of theocular condition by, for example, causing an intra-ocular pressuredepression.

Example 12 Preparation and Therapeutic Use of an Alpha-2 ExtendedRelease Implant(s)

An extended release implant system can be used to treat an ocularcondition wherein the implant contains as the active agent an alpha-2adrenergic receptor agonist, such as clonidine, apraclonidine, orbrimonidine. Thus, an extended release bioerodible implant systemcontaining brimonidine (Allergan, Irvine, Calif., as Alphagan orAlphagan P) as the active agent can be made using the method of Example1 or the method of Example 4, but with use of Alphagan instead ofdexamethasone. Thus, about 50 μg to 100 μg of Alphagan can be loadedinto each of the three implants prepared according to the Example 1method.

The brimonidine extended release implant system can be implanted into anocular region or site (i.e. into the vitreous) of a patient with anocular condition for a desired therapeutic effect. The ocular conditioncan be an inflammatory condition such as uveitis or the patient can beafflicted with one or more of the following afflictions: maculardegeneration (including non-exudative age related macular degenerationand exudative age related macular degeneration); choroidalneovascularization; acute macular neuroretinopathy; macular edema(including cystoid macular edema and diabetic macular edema); Behcet'sdisease, diabetic retinopathy (including proliferative diabeticretinopathy); retinal arterial occlusive disease; central retinal veinocclusion; uveitic retinal disease; retinal detachment; retinopathy; anepiretinal membrane disorder; branch retinal vein occlusion; anteriorischemic optic neuropathy; non-retinopathy diabetic retinal dysfunction,retinitis pigmentosa and glaucoma. The implant(s) can be inserted intothe vitreous using the procedure (trocar implantation) set forth inExample 2 and 6. The implant(s) can release a therapeutic amount of thebrimonidine for an extended period of time to thereby treat a symptom ofthe ocular condition by, for example, causing an intra-ocular pressuredepression.

Example 13 Preparation and Therapeutic Use of a Retinoid ExtendedRelease Implant(s)

An extended release implant system can be used to treat an ocularcondition. The implant can contain a retinoid such as an ethylnicotinate, such as a tazarotene. Thus, an extended release bioerodibleimplant system containing tazarotene (Allergan, Irvine, Calif.) as theactive agent can be made using the method of Example 1 or the method ofExample 4, but with use of tazarotene instead of dexamethasone. Thus,about 100 μg to 500 μg of tazarotene can be loaded into each of thethree implants prepared according to the Example 1 method.

The tazarotene extended release implant system can be implanted into anocular region or site (i.e. into the vitreous) of a patient with anocular condition for a desired therapeutic effect. The ocular conditioncan be an inflammatory condition such as uveitis or the patient can beafflicted with one or more of the following afflictions: maculardegeneration (including non-exudative age related macular degenerationand exudative age related macular degeneration); choroidalneovascularization; acute macular neuroretinopathy; macular edema(including cystoid macular edema and diabetic macular edema); Behcet'sdisease, diabetic retinopathy (including proliferative diabeticretinopathy); retinal arterial occlusive disease; central retinal veinocclusion; uveitic retinal disease; retinal detachment; retinopathy; anepiretinal membrane disorder; branch retinal vein occlusion; anteriorischemic optic neuropathy; non-retinopathy diabetic retinal dysfunction,retinitis pigmentosa and glaucoma. The implant(s) can be inserted intothe vitreous using the procedure (trocar implantation) set forth inExample 2 and 6. The implant(s) can release a therapeutic amount of thetazarotene for an extended period of time to thereby treat a symptom ofthe ocular condition by, for example, causing an intra-ocular pressuredepression.

Example 14 Preparation and Therapeutic Use of a Tyrosine KinaseInhibitor Extended Release Implant(s)

Generally, tyrosine kinase inhibitors are small molecule inhibitors ofgrowth factor signaling. Protein tyrosine kinases (PTKs) comprise alarge and diverse class of proteins having enzymatic activity. The PTKsplay an important role in the control of cell growth anddifferentiation. For example, receptor tyrosine kinase mediated signaltransduction is initiated by extracellular interaction with a specificgrowth factor (ligand), followed by receptor dimerization, transientstimulation of the intrinsic protein tyrosine kinase activity andphosphorylation. Binding sites are thereby created for intracellularsignal transduction molecules and lead to the formation of complexeswith a spectrum of cytoplasmic signaling molecules that facilitate theappropriate cellular response (e.g., cell division, metabolichomeostasis, and responses to the extracellular microenvironment).

With respect to receptor tyrosine kinases, it has been shown also thattyrosine phosphorylation sites function as high-affinity binding sitesfor SH2 (src homology) domains of signaling molecules. Severalintracellular substrate proteins that associate with receptor tyrosinekinases (RTKs) have been identified. They may be divided into twoprincipal groups: (1) substrates which have a catalytic domain; and (2)substrates which lack such domain but serve as adapters and associatewith catalytically active molecules. The specificity of the interactionsbetween receptors or proteins and SH2 domains of their substrates isdetermined by the amino acid residues immediately surrounding thephosphorylated tyrosine residue. Differences in the binding affinitiesbetween SH2 domains and the amino acid sequences surrounding thephosphotyrosine residues on particular receptors are consistent with theobserved differences in their substrate phosphorylation profiles. Theseobservations suggest that the function of each receptor tyrosine kinaseis determined not only by its pattern of expression and ligandavailability but also by the array of downstream signal transductionpathways that are activated by a particular receptor. Thus,phosphorylation provides an important regulatory step which determinesthe selectivity of signaling pathways recruited by specific growthfactor receptors, as well as differentiation factor receptors.

Aberrant expression or mutations in the PTKs have been shown to lead toeither uncontrolled cell proliferation (e.g. malignant tumor growth) orto defects in key developmental processes. Consequently, the biomedicalcommunity has expended significant resources to discover the specificbiological role of members of the PTK family, their function indifferentiation processes, their involvement in tumorigenesis and inother diseases, the biochemical mechanisms underlying their signaltransduction pathways activated upon ligand stimulation and thedevelopment of novel drugs.

Tyrosine kinases can be of the receptor-type (having extracellular,transmembrane and intracellular domains) or the non-receptor type (beingwholly intracellular). The RTKs comprise a large family of transmembranereceptors with diverse biological activities. The intrinsic function ofRTKs is activated upon ligand binding, which results in phophorylationof the receptor and multiple cellular substrates, and subsequently in avariety of cellular responses.

At present, at least nineteen (19) distinct RTK subfamilies have beenidentified. One RTK subfamily, designated the HER subfamily, is believedto be comprised of EGFR, HER2, HER3 and HER4. Ligands to the Hersubfamily of receptors include epithelial growth factor (EGF), TGF-α,amphiregulin, HB-EGF, betacellulin and heregulin.

A second family of RTKs, designated the insulin subfamily, is comprisedof the INS-R, the IGF-1R and the IR-R. A third family, the “PDGF”subfamily includes the PDGF α and β receptors, CSFIR, c-kit and FLK-II.Another subfamily of RTKs, identified as the FLK family, is believed tobe comprised of the Kinase insert Domain-Receptor fetal liver kinase-1(KDR/FLK-1), the fetal liver kinase 4 (FLK-4) and the fms-like tyrosinekinase 1 (flt-1). Each of these receptors was initially believed to bereceptors for hematopoietic growth factors. Two other subfamilies ofRTKs have been designated as the FGF receptor family (FGFR1, FGFR2,FGFR3 and FGFR4) and the Met subfamily (c-met and Ron).

Because of the similarities between the PDGF and FLK subfamilies, thetwo subfamilies are often considered together. The known RTK subfamiliesare identified in Plowman et al, 1994, DN&P 7(6): 334-339, which isincorporated herein by reference.

The non-receptor tyrosine kinases represent a collection of cellularenzymes which lack extracellular and transmembrane sequences. Atpresent, over twenty-four individual non-receptor tyrosine kinases,comprising eleven (11) subfamilies (Src, Frk, Btk, Csk, Abl, Zap70,Fes/Fps, Fak, Jak, Ack and LIMK) have been identified. At present, theSrc subfamily of non-receptor tyrosine kinases is comprised of thelargest number of PTKs and include Src, Yes, Fyn, Lyn, Lck, Blk, Hck,Fgr and Yrk. The Src subfamily of enzymes has been linked tooncogenesis. A more detailed discussion of non-receptor tyrosine kinasesis provided in Bolen, 1993, Oncogene 8: 2025-2031, which is incorporatedherein by reference.

Many of the tyrosine kinases, whether an RTK or non-receptor tyrosinekinase, have been found to be involved in cellular signaling pathwaysleading to cellular signal cascades leading to pathogenic conditions,including cancer, psoriasis and hyper immune response.

In view of the surmised importance of PTKs to the control, regulationand modulation of cell proliferation the diseases and disordersassociated with abnormal cell proliferation, many attempts have beenmade to identify receptor and non-receptor tyrosine kinase “inhibitors”using a variety of approaches, including the use of mutant ligands (U.S.Pat. No. 4,966,849), soluble receptors and antibodies (PCT ApplicationNo. WO 94/10202; Kendall & Thomas, 1994, Proc. Nat'l Acad. Sci 90:10705-09; Kim, et al, 1993, Nature 362: 841-844), RNA ligands (Jellinek,et al, Biochemistry 33: 10450-56); Takano, et al, 1993, Mol. Bio. Cell4:358A; Kinsella, et al, 1992, Exp. Cell Res. 199: 56-62; Wright, et al,1992, J. Cellular Phys. 152: 448-57) and tyrosine kinase inhibitors (PCTApplication Nos. WO 94/03427; WO 92/21660; WO 91/15495; WO 94/14808;U.S. Pat. No. 5,330,992; Mariani, et al, 1994, Proc. Am. Assoc. CancerRes. 35: 2268).

An extended release implant system can be used to treat an ocularcondition wherein the implant contains a tyrosine kinase inhibitor (TKI)such as a TKI set forth in published U.S. patent application 200400019098 (available from Allergan, Irvine, Calif.) as the active agentcan be made using the method of Example 1 or the method of Example 4,but with use of a TKI instead of dexamethasone. Thus, about 100 μg to300 μg of a TKI can be loaded into each of the three implants preparedaccording to the Example 1 method.

The TKI extended release implant system can be implanted into an ocularregion or site (i.e. into the vitreous) of a patient with an ocularcondition for a desired therapeutic effect. The ocular condition can bean inflammatory condition such as uveitis or the patient can beafflicted with one or more of the following afflictions: maculardegeneration (including non-exudative age related macular degenerationand exudative age related macular degeneration); choroidalneovascularization; acute macular neuroretinopathy; macular edema(including cystoid macular edema and diabetic macular edema); Behcet'sdisease, diabetic retinopathy (including proliferative diabeticretinopathy); retinal arterial occlusive disease; central retinal veinocclusion; uveitic retinal disease; retinal detachment; retinopathy; anepiretinal membrane disorder; branch retinal vein occlusion; anteriorischemic optic neuropathy; non-retinopathy diabetic retinal dysfunction,retinitis pigmentosa and glaucoma. The implant(s) can be inserted intothe vitreous using the procedure (trocar implantation) set forth inExample 2 and 6. The implant(s) can release a therapeutic amount of theTKI for an extended period of time to thereby treat a symptom of theocular condition by, for example, causing an intra-ocular pressuredepression.

Example 15 Preparation and Therapeutic Use of an NMDA AntagonistExtended Release Implant(s)

It is believed that overstimulation of the N-methyl-D-aspartate (NMDA)receptor by glutamate is implicated in a variety of disorders. Memantineis an NMDA antagonist which can be used to reduce neuronal damagemediated by the NMDA receptor complex.

Memantine is a available form Merz Pharmaceuticals, Greensboro, N.C.under the trade name Axura. An extended release implant system can beused to treat an ocular condition. The implant can contain an NMDAantagonist such as memantine. Thus, an extended release bioerodibleimplant system containing memantine as the active agent can be madeusing the method of Example 1 or the method of Example 4, but with useof memantine instead of dexamethasone. Thus, about 400 μg to 700 μg ofmemantine can be loaded into each of the three implants preparedaccording to the Example 1 method.

The memantine extended release implant system can be implanted into anocular region or site (i.e. into the vitreous) of a patient with anocular condition for a desired therapeutic effect. The ocular conditioncan be an inflammatory condition such as uveitis or the patient can beafflicted with one or more of the following afflictions: maculardegeneration (including non-exudative age related macular degenerationand exudative age related macular degeneration); choroidalneovascularization; acute macular neuroretinopathy; macular edema(including cystoid macular edema and diabetic macular edema); Behcet'sdisease, diabetic retinopathy (including proliferative diabeticretinopathy); retinal arterial occlusive disease; central retinal veinocclusion; uveitic retinal disease; retinal detachment; retinopathy; anepiretinal membrane disorder; branch retinal vein occlusion; anteriorischemic optic neuropathy; non-retinopathy diabetic retinal dysfunction,retinitis pigmentosa and glaucoma. The implant(s) can be inserted intothe vitreous using the procedure (trocar implantation) set forth inExample 2 and 6. The implant(s) can release a therapeutic amount of thememantine for an extended period of time to thereby treat a symptom ofthe ocular condition.

Example 16 Preparation and Therapeutic Use of an Estratropone ExtendedRelease Implant(s)

Certain estratropones have anti-angiogenesis, anti-neoplastic andrelated useful therapeutic activities. An extended release implantsystem can be used to treat an ocular condition. The implant can containan estratropone such as 2-methoxyestradiol (available form Entremed,Inc., of Rockville, Md. under the tradename Panzem). Thus, an extendedrelease bioerodible implant system containing memantine as the activeagent can be made using the method of Example 1 or the method of Example4, but with use of 2-methoxyestradiol instead of dexamethasone.2-methoxyestradiol can be used as a small molecule angiogenic inhibitorto block abnormal blood vessel formation in the back of the eye. Thus,about 400 μg to 700 μg of 2-methoxyestradiol can be loaded into each ofthe three implants prepared according to the Example 1 method.

The 2-methoxyestradiol extended release implant system can be implantedinto an ocular region or site (i.e. into the vitreous) of a patient withan ocular condition for a desired therapeutic effect. The ocularcondition can be an inflammatory condition such as uveitis or thepatient can be afflicted with one or more of the following afflictions:macular degeneration (including non-exudative age related maculardegeneration and exudative age related macular degeneration); choroidalneovascularization; acute macular neuroretinopathy; macular edema(including cystoid macular edema and diabetic macular edema); Behcet'sdisease, diabetic retinopathy (including proliferative diabeticretinopathy); retinal arterial occlusive disease; central retinal veinocclusion; uveitic retinal disease; retinal detachment; retinopathy; anepiretinal membrane disorder; branch retinal vein occlusion; anteriorischemic optic neuropathy; non-retinopathy diabetic retinal dysfunction,retinitis pigmentosa and glaucoma. The implant(s) can be inserted intothe vitreous using the procedure (trocar implantation) set forth inExample 2 and 6. The implant(s) can release a therapeutic amount of the2-methoxyestradiol for an extended period of time to thereby treat asymptom of the ocular condition.

Using the same methodology, additional extended release single ormultiple polymer implants can be prepared wherein the active agent is,for example, an agent to treat intravitreal hemorrhage (such as Vitrase,available from Ista Pharmaceuticals), an antibiotic (such ascyclosporine, or gatifloxacin, the former being available from Allergan,Irvine, Calif. under the tradename Restasis and the later from Allerganunder the tradename Zymar), ofloxacin, an androgen, epinastine (Elestat,Allergan, Irvine, Calif.), or with a combination of two or more activeagents (such as a combination in a single extended release implant of aprostamide (i.e. bimatoprost) and a best blocker (i.e. timolol) or acombination of an alpha 2 adrenergic agonist (i.e. brimonidine) and abeta blocker, such as timolol) in the same extended delivery system. Animplant within the scope of the present invention can be used inconjunction with a photodynamic therapy or laser procedure upon an eyetissue.

All references, articles, patents, applications and publications setforth above are incorporated herein by reference in their entireties.

Accordingly, the spirit and scope of the following claims should not belimited to the descriptions of the preferred embodiments set forthabove.

We claim:
 1. An extended release solid extruded bioerodible implant fortreating an ocular condition in a subject, the implant made by a methodcomprising the steps of: (a) blending an active agent with a firstbioerodible polymer; (b) extruding the blend of step (a) to form afilament; (c) breaking the extruded filament of step (b) into particleswith a size of between about 30 μm and about 50 μm; (d) blendingadditional quantities of the active agent with a second bioerodiblepolymer; (e) mixing the particles of step (c) with the blend of step(d): (f) extruding the mixture of step (e) to form a filament; and (g)cutting the filament of step (f) to form an extended release bioerodibleimplant for insertion into an ocular region or site of the subject;wherein the active agent is dexamethasone; the first bioerodible polymeris R203, which is a poly(D,L-lactide) having a molecular weight of about14,000; and the second bioerodible polymer is selected from the groupconsisting of RG502, which is a poly(D,L-lactide-co-glycolide) having amolecular weight of about 11,700 and a lactide:glycolide content ofabout 50:50 by weight, and RG502H, which is apoly(D,L-lactide-co-glycolide) having a molecular weight of about 8,500,a lactide:glycolide content of about 50:50 by weight, and a free acid atthe end of the polymer chain.
 2. The implant of claim 1, wherein theimplant formed in step (g) has a diameter of about 0.05 mm to about 3 mmand a length of about 0.5 to about 10 mm.
 3. The implant of claim 1,which when administered into the ocular region or site of the subject,releases a therapeutic level of the therapeutic agent into the ocularregion or site for a period of time of between about 30 days and about 1year.